Pyrazolopyrimidine derivatives and pharmaceutical compositions containing them

ABSTRACT

The present invention provides compounds of formula (I): 
                         
pharmaceutical compositions containing the same, processes for preparing the same and their use as pharmaceutical agents.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a 371 Application of PCT/US03/05704, filed 24 Feb.2003, which claims priority to U.S. Application Ser. No. 60/362,298,filed 7 Mar. 2002.

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds, pharmaceuticalformulations comprising these compounds, and the use of these compoundsin therapy. More particularly, the present invention relates tocompounds for the prophylaxis and treatment of herpes viral infections.

Of the DNA viruses, those of the herpes group are the sources of themost common viral illnesses in man. The group includes herpes simplexvirus types 1 and 2 (HSV), varicella zoster virus (VZV), cytomegalovirus(CMV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6),human herpes virus type 7 (HHV-7) and human herpes virus type 8 (HHV-8).HSV-1 and HSV-2 are some of the most common infectious agents of man.Most of these viruses are able to persist in the host's neural cells;once infected, individuals are at risk of recurrent clinicalmanifestations of infection which can be both physically andpsychologically distressing.

Herpes simplex viruses (HSV-1 and -2) are the causative agents of herpeslabialis and genital herpes. HSV infection is often characterised byextensive and debilitating lesions of the skin, mouth and/or genitals.Primary infections may be subclinical although tend to be more severethan infections in individuals previously exposed to the virus. Ocularinfection by HSV can lead to keratitis or cataracts thereby endangeringthe host's sight. Infection in the new-born, in immunocompromisedpatients or penetration of the infection into the central nervous systemcan prove fatal. In the US alone, 40 million individuals are infectedwith HSV-2. a number that is expected to increase to 60 million by 2007.Over 80% of individuals infected with HSV-2 are unaware they carry andspread the virus, and of those diagnosed less than 20% received oraltherapies. The net result is that less than 5% of the infectedpopulation are treated. Likewise of the 530 million individualsworldwide who carry HSV-1, 81% of the symptomatic population remainuntreated. No cure exists for HSV infection, and once infected,individuals carry the virus for life in a dormant state. Reactivation ofthe virus from latency occurs periodically and may be triggered bystress, environmental factors, and/or suppression of the host immunesystem. Currently, the use of nucleoside analogs such as valaciclovir(VALTREX®) and aciclovir (ZOVIRAX®) is the standard of care for managinggenital herpes virus outbreaks.

Varicella zoster virus (VZ) (also know as herpes zoster virus) is aherpes virus which causes chickenpox and shingles. Chickenpox is theprimary disease produced in a host without immunity, and in youngchildren is usually a mild illness characterised by a vesicular rash andfever. Shingles or zoster is the recurrent form of the disease whichoccurs in adults who were previously infected with VZV. The clinicalmanifestations of shingles are characterised by neuralgia and avesicular skin rash that is unilateral and dermatomal in distribution.Spread of inflammation may lead to paralysis or convulsions. Coma canoccur if the meninges become affected. VZV is of serious concern inpatients receiving immunosuppressive drugs for transplant purposes orfor treatment of malignant neoplasia and is a serious complication ofAIDS patients due to their impaired immune system.

In common with other herpes viruses, infection with CMV leads to alifelong association of virus and host Congenital infection followinginfection of the mother during pregnancy may give rise to clinicaleffects such as death or gross disease (microcephaly,hepatosplenomegaly, jaundice, mental retardation), retinitis leading toblindness or, in less severe forms, failure to thrive, andsusceptibility to chest and ear infections. CMV infection in patientswho are immunocompromised for example as a result of malignancy,treatment with immunosuppressive drugs following transplantation orinfection with Human Immunodeficiency Virus, may give rise to retinitis,pneumonitis, gastrointestinal disorders and neurological diseases. CMVinfection is also associated with cardiovascular diseases and conditionsincluding restenosis and atherosclerosis.

The main disease caused by EBV is acute or chronic infectiousmononucleosis (glandular fever). Examples of other EBV or EBV associateddiseases include lymphoproliferative disease which frequently occurs inpersons with congenital or acquired cellular immune deficiency, X-linkedlymphoproliferative disease which occurs namely in young boys,EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngealcarcinoma, Burkitt lymphoma, non-Hodgkin lymphoma, thymomas and oralhairy leukoplakia. EBV infections have also been found in associationwith a variety of epithelial-cell-derived tumours of the upper and lowerrespiratory tracts including the lung. EBV infection has also beenassociated with other diseases and conditions including chronic fatiguesyndrome, multiple sclerosis and Alzheimer's disease.

HHV-6 has been shown to be a causative agent of infantum subitum inchildren and of kidney rejection and interstitial pneumonia in kidneyand bone marrow transplant patients, respectively, and may be associatedwith other diseases such as multiple sclerosis. There is also evidenceof repression of stem cell counts in bone marrow transplant patients.HHV-7 is of undetermined disease aetiology.

Hepatitis B virus (HBV) is a viral pathogen of world-wide majorimportance. The virus is aetiologically associated with primaryhepatocellular carcinoma and is thought to cause 80% of the world'sliver cancer. Clinical effects of infection with HBV range fromheadache, fever, malaise, nausea, vomiting, anorexia and abdominalpains. Replication of the virus is usually controlled by the immuneresponse, with a course of recovery lasting weeks or months in humans,but infection may be more severe leading to persistent chronic liverdisease outlined above.

BRIEF SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided compoundsof formula (I):

wherein:

-   R¹ is selected from the group consisting of H, halo, alkyl, alkenyl,    alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay,    —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹,    —R¹⁰(C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹ ₁, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and    azido;    -   each R⁷ and R⁹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰Ay, —R¹⁰Het, —R¹⁰OC(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹,        —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰SO₂R¹⁰ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl, and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y¹ is N or CH;-   p is 0, 1 or 2 when Y¹ is CH,-   p is 0 or 1 when Y¹ is N;-   each R⁶ is the same or different and is independently selected from    the group consisting of H, halo, alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het,    —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹,    —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and    azido;    -   or when p is 2, two adjacent R⁶ groups together with the carbon        atoms to which they are bonded form a cycloalkyl or a 5- or        6-membered heterocyclic group containing 1 or 2 heteroatoms;-   Y is N or CH;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay,    —NHHet —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, alkenyl,    cycloalkyl, Ay, Het, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy,    —NR⁷R⁸, —NR⁷Ay, —NHHet, —SO₂NHR⁹, —R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy,    —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   Ring A is selected from the group consisting of aryl, 5–10 membered    heterocyclic group and a 5–10 membered heteroaryl group;-   q is 0, 1, 2, 3, 4 or 5; and-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸ ₁, —C(NH)NR⁷Ay,    —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,    —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, cyano, nitro and azido; and-   pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

According to another aspect, the present invention provides apharmaceutical composition comprising a compound of formula (I). In oneembodiment, the pharmaceutical composition further comprises apharmaceutically acceptable carrier or diluent. In one embodiment, thepharmaceutical composition further comprises an antiviral agent selectedfrom the group consisting of aciclovir and valaciclovir.

According to a third aspect, the present invention provides a method forthe prophylaxis or treatment of a herpes viral infection in an animal.The method comprises administering to the animal a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof. The herpes viral infection may be herpes simplex virus 1,herpes simplex virus 2, cytomegalovirus, Epstein Barr virus, varicellazoster virus, human herpes virus 6, human herpes virus 7, or humanherpes virus 8.

According to a fourth aspect, the present invention provides a methodfor the prophylaxis or treatment of a condition or disease associatedwith a herpes viral infection in an animal. The method comprisesadministering to the animal a therapeutically effective amount of thecompound of formula (I) or a pharmaceutically acceptable salt, solvateor physiologically functional derivative thereof.

According to a fifth aspect, the present invention provides a processfor preparing a compound of formula (I) wherein Y¹ is CH; Y is N; R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NHHet—S(O)_(n)R⁹ ₁, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ areH. The process comprises reacting a compound of formula (XX):

with a compound of formula (XXI):

According to a sixth aspect, the present invention provides a processfor preparing a compound of formula (I) wherein Y is N; R² is selectedfrom the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl,Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NHHet —S(O)_(n)R⁹,—S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected from the groupconsisting of H, alkyl, alkenyl, cycloalkyl, Ay, Het, —C(O)R⁷, C(O)Ay,—CO₂R⁷, —CO₂Ay, —OR⁷, —OAy, —NR⁷R⁸ (where R⁷ and R⁸ are not H), —NR⁷Ay(where R⁷ is H), —SO₂NHR⁹, —R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy, —R¹⁰NR⁷R⁸and —R¹⁰NR⁷Ay; and R⁴ is H. The process comprises reacting a compound offormula (XXV):

with a compound of formula (XXI):

According to a seventh aspect, the present invention provides a processfor preparing a compound of formula (I) wherein Y is N and R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NHHet—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay. The process comprisesthe steps of:

-   a) reacting a compound of formula (XXVIII):

-    with a compound of formula (XXI):

-    to prepare an intermediate compound; and-   b) oxidizing the intermediate compound.

According to an eighth aspect, the present invention provides a processfor preparing a compound of formula (I). The process comprises reactinga compound of formula (XXX):

-   -   wherein X¹ is chloro, bromo or iodo;        with a compound of formula (X):

-   -   wherein M¹ is —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide,        ZnRa, or Mg-halide where Ra is alkyl or cycloalkyl and halide is        halo.

As another aspect, the present invention provides a process comprisingthe further step of converting the compound of formula (I) to apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof. In another aspect, the present invention provides aprocess comprising the further step of converting the compound offormula (I) or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof to another compound offormula (I) or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof.

According to another aspect, the present invention provides aradiolabeled compound of formula (I) or a pharmaceutically acceptablesalt, solvate or physiologically functional derivative thereof. In oneembodiment, the radiolabeled compound is tritiated. In another aspect,the present invention provides a biotinylated compound of formula (I) ora pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof.

According to another aspect, the present invention provides a compoundof formula (I) for use in therapy. The present invention also provides acompound of formula (I) for the prophylaxis or treatment of a herpesviral infection in an animal. The present invention also provides acompound of formula (I) for the prophylaxis or treatment of a conditionor disease associated with a herpes viral infection in an animal.

According to another aspect, the present invention provides the use of acompound of formula (I) for the preparation of a medicament forprophylaxis or treatment of a herpes viral infection in an animal,preferably humans. The present invention also provides the use of acompound of formula (I) for the preparation of a medicament for theprophylaxis or treatment of a condition or disease associated with aherpes viral infection in an animal, preferably humans.

According to another aspect, the present invention provides apharmaceutical composition comprising a compound of formula (I) for usein the prophylaxis or treatment of herpes viral infections in an animal.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “a compound of the invention” or “a compound of formula(I)” means a compound of formula (I) or a pharmaceutically acceptablesalt, solvate, or physiologically functional derivative thereof.Similarly, with respect to isolatable intermediates such as for example,compounds of formula (IX), (XII), (XX), (XXV), (XXVIII) and (XXX), thephrase “a compound of formula (number)” means a compound having thatformula and pharmaceutically acceptable salts, solvates andphysiologically functional derivatives thereof.

As used herein, the terms “alkyl” (or “alkylene”) refer to straight orbranched hydrocarbon chains containing from 1 to 8 carbon atoms.Examples of “alkyl” as used herein include, but are not limited to,methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, andtert-butyl. Examples of “alkylene” as used herein include, but are notlimited to, methylene, ethylene, propylene, butylene, and isobutylene.“Alkyl” also includes substituted alkyl. The alkyl groups may beoptionally substituted with one or more substituents selected from thegroup consisting of mercapto, nitro, cyano, azido and halo.Perhaloalkyl, such as trifluoromethyl, is one preferred alkyl group.

As used herein, the term “cycloalkyl” (or “cycloalkylene”) refers to anon-aromatic carbocyclic ring having from 3 to 8 carbon atoms and nocarbon-carbon double bonds. “Cycloalkyl” includes by way of examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. “Cycloalkyl” also includes substituted cycloalkyl. Thecycloalkyl may optionally be substituted on an available carbon with oneor more substituents selected from the group consisting of mercapto,nitro, cyano, halo, and alkyl.

As used herein, the term “alkenyl” (or “alkenylene”) refers to straightor branched hydrocarbon chains containing from 2 to 8 carbon atoms andat least one and up to three carbon-carbon double bonds. Examples of“alkenyl” as used herein include, but are not limited to ethenyl andpropenyl. “Alkenyl” also includes substituted alkenyl. The alkenylgroups may optionally be substituted on an available carbon with one ormore substituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

As used herein, the term “cycloalkenyl” (or “cycloalkenylene”) refers torefers to a non-aromatic carbocyclic ring having from 3 to 8 carbonatoms (unless otherwise specified) and up to 3 carbon-carbon doublebonds. “Cycloalkenyl” includes by way of example cyclobutenyl,cyclopentenyl and cyclohexenyl. “Cycloalkenyl” also includes substitutedcycloalkenyl. The cycloalkenyl may optionally be substituted on anavailable carbon with one or more substituents selected from the groupconsisting of mercapto, nitro, cyano, halo, and alkyl.

As used herein, the term “alkynyl” (or “alkynylene”) refers to straightor branched hydrocarbon chains containing from 2 to 8 carbon atoms andat least one and up to three carbon-carbon triple bonds. Examples of“alkynyl” as used herein include, but are not limited to ethynyl andpropynyl. “Alkynyl” also includes substituted alkynyl. The alkynylgroups may optionally be be substituted on an available carbon with oneor more substituents selected from the group consisting of mercapto,nitro, cyano, halo, and alkyl.

The term “halo” or “halogen” refers to the elements fluorine, chlorine,bromine and iodine.

The term “aryl” refers to monocyclic carbocyclic groups and fusedbicyclic carbocyclic groups having from 5 to 12 carbon atoms and havingat least one aromatic ring. Examples of particular aryl groups includebut are not limited to phenyl and naphthyl. “Aryl” also includessubstituted aryl. Aryl groups may optionally be substituted on anavailable carbon with one or more substituents selected from the groupconsisting of halo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl,cycloalkenyl, alkoxy, cycloalkoxy, amino, mercapto, hydroxy,alkylhydroxy, alkylamine, cycloalkylamine, carboxy, carboxamide,sulfonamide, Het, amidine, cyano, nitro and azido. Preferred aryl groupsaccording to the invention include but are not limited to phenyl andsubstituted phenyl.

The term “heterocyclic” (or “heterocycle”) refers to a monocyclicsaturated or unsaturated non-aromatic groups and fused bicyclicnon-aromatic groups, having the specified number of members andcontaining 1, 2, 3 or 4 heteroatoms selected from N, O and S. Examplesof particular heterocyclic groups include but are not limited totetrahydrofuran, dihydropyran, tetrahydropyran, pyran, oxetane,thietane, 1,4-dioxane, 1,3-dioxane, 1,3-dioxalane, piperidine,piperazine, tetrahydropyrimidine, pyrrolidine, morpholine,thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran,tetrahydrothiophene, and the like. “Heterocyclic” also includessubstituted heterocyclic. The heterocyclic group may be optionallysubstituted on an available carbon or heteroatom, with one or moresubstituents selected from the group consisting of halo, alkyl(including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy,cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine,cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano,nitro and azido. Preferred heterocyclic groups according to theinvention include but are not limited to pyrrolidine, piperidine,morpholine, thiomorpholine and piperazine and substituted variantsthereof.

The term “heteroaryl” refers to aromatic monocyclic groups and aromaticfused bicyclic groups having the specified number of members andcontaining 1, 2, 3, or 4 heteroatoms selected from N, O and S. Examplesof particular heteroaryl groups include but are not limited to furan,thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole,oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine,pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran,benzothiophene, indole, and indazole. “Heteroaryl” also includessubstituted heteroaryl. The heteroaryl group may optionally besubstituted on an available carbon or heteroatom with one or moresubstituents selected from the group consisting of halo, alkyl(including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy,cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine,cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano,nitro and azido. Preferred heteroaryl groups according to the inventioninclude but are not limited to pyridine, furan, thiophene, pyrrole,imidazole, pyrazole and pyrimidine, and substituted variants thereof.

The term “members” or “membered” in the context of heterocyclic andheteroaryl groups refers to the total atoms, carbon and heteroatoms N, Oand/or S, which form the ring. Thus, an example of a 6-memberedheterocyclic ring is piperidine and an example of a 6-memberedheteroaryl ring is pyridine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

The present invention provides compounds of formula (I):

wherein:

-   R¹ is selected from the group consisting of H, halo, alkyl, alkenyl,    alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay,    —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹,    —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and    azido;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)N R⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰Ay, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹,        —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰SO₂R¹⁰ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl, and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y¹ is N or CH;-   p is 0, 1 or 2 when Y¹ is CH,-   p is 0 or 1 when Y¹ is N;-   each R⁶ is the same or different and is independently selected from    the group consisting of H, halo, alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het,    —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹,    —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and    azido;    -   or when p is 2 (and Y′ is CH), two adjacent R⁶ groups together        with the carbon atoms to which they are bonded form a cycloalkyl        or a 5- or 6-membered heterocyclic group containing 1 or 2        heteroatoms;-   Y is N or CH;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay,    —NHHet —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, alkenyl,    cycloalkyl, Ay, Het, —C(O)R⁷, C(O)Ay, —CO₂R⁷ ₁, —CO₂Ay, —OR⁷, —OAy,    —NR⁷R⁸, —NR⁷Ay, —NHHet, —SO₂NHR⁹, —R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy,    —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   Ring A is selected from the group consisting of aryl, 5–10 membered    heterocyclic group and a 5–10 membered heteroaryl group;-   q is 0, 1, 2, 3, 4 or 5; and-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷,    —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,    —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, cyano, nitro and azido; and    pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

In one embodiment of the invention R¹ contains an aryl, heterocyclic orheteroaryl moiety (e.g., R¹ is selected from the group consisting of Ay,Het, —C(O)Ay, —C(O)Het, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(NH)NR⁷R⁸,—C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)Ay,—S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰Ay, —R¹⁰Het, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het (where R⁷ or R⁸ is appropriately definedto provide a group containing an aryl, heterocyclic or heteroarylmoiety), or any subset thereof). In another embodiment, compounds offormula (I) are defined wherein R¹ contains a heterocyclic or heteroarylmoiety (e.g., R¹ is selected from the group consisting of Het, —C(O)Het,—C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(NH)NR⁷R⁸, —OR⁷, —OHet, —NR⁷R⁸, —NHHet,—S(O)_(n)Het, —S(O)₂NR⁷R⁸, —R¹⁰Het, —R¹⁰NR⁷R⁸, —R¹⁰C(O)Het, —R¹⁰OC(O)Hetand —R¹⁰C(O)NHR¹⁰Het (where R⁷ or R⁸ is appropriately defined to providea group containing a heterocyclic or heteroaryl moiety), or any subsetthereof). In yet another embodiment, the compounds of formula (I) aredefined wherein R¹ does not contain an aryl, heterocyclic or heteroarylmoiety (e.g., R¹ is selected from the group consisting of H, halo,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹,—C(O)NR⁷R⁸, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —OR⁷, —NR⁷R⁸, —S(O)_(n)R⁹,—S(O)₂NR⁷R⁸, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NHSO₂R⁹,—R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹,—R¹⁰OS(O)_(n)R⁹, cyano, nitro and azido (where R⁷ and R⁸ areappropriately defined to provide a group that does not contain an aryl,heterocyclic or heteroaryl moiety), or any subset thereof). In anotherembodiment, R¹ may contain an aryl moiety but does not contain aheteroaryl or heterocyclic moiety (e.g., R¹ is selected from the groupconsisting of H, halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, —C(O)R⁹, —C(O)Ay, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay,—C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷, —OAy, —NR⁷R⁸, —NR⁷Ay,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,—R¹⁰Ay, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹, —R¹⁰C(O)R⁹,—R¹⁰C(O)Ay, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹, —R¹⁰OC(O)Ay, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and azido(where R⁷ and R⁸ are appropriately defined to provide a group that doesnot contain a heterocyclic or heteroaryl moiety), or any subsetthereof).

In one embodiment, R¹ is selected from the group consisting of halo,alkyl, cycloalkyl, Ay, Het, —OR⁷, —OAy, —NR⁷R⁸, —NR⁷Ay, —NHHet,—S(O)_(n)R⁹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, or anysubset thereof. More particularly, R¹ is selected from the groupconsisting of halo, alkyl, Het, —OR⁷, —NR⁷R⁸, —NR⁷Ay, —NHHet and—S(O)_(n)R⁹, or any subset thereof. In one particular embodiment R¹ isselected from the group consisting of alkyl, Het, —OR⁷, —NR⁷R⁸, —NR⁷Ayand —S(O)_(n)R⁹, or any subset thereof. In one embodiment, R¹ is —NR⁷R⁸.

More specifically, particular compounds of formula (I) are definedwherein R¹ is selected from the group consisting of halo, alkyl, —NH₂,—NH-alkyl, —NH-cycloalkyl, —N(alkyl)(alkyl), Het, —O-alkyl,—NHalkyl—O—alkyl, —NHAy and —S-alkyl, or any subset thereof. Moreparticularly, R¹ is selected from the group consisting of —NH-alkyl,—NH-cycloalkyl and pyrrolidine or any subset thereof. Specific examplesof some R¹ groups are selected from the group consisting of Cl, ethyl,propyl, isopropyl, butyl, isobutyl, —NH-methyl, —N(CH₃)₂,—NH-cyclopentyl, —NH-cyclopropyl, —NH-isopropyl, —NH-butyl, —NH-phenyl,—NH(CH₂)₂OCH₃, methoxy, ethoxy, propoxy, isopropoxy, butoxy,thiomethoxy, thioethoxy, thioisopropoxy and pyrrolidine, or any subsetthereof.

In one embodiment, R⁷ and R⁸ are each the same or different and are eachindependently selected from the group consisting of H, alkyl,cycloalkyl, —C(O)R⁹, —R¹⁰-cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹,—R¹⁰NR⁹R¹¹, and —R¹⁰CO₂R⁹, or any subset thereof. More particularly insuch embodiment, R⁷ and R⁸ are each the same or different and are eachindependently selected from the group consisting of H, alkyl,cycloalkyl, —R¹⁰-cycloalkyl, —R¹⁰Ay and —R¹⁰Het, or any subset thereof.In one particular embodiment, R⁷ and R⁸ are each the same or differentand are each independently selected from the group consisting of H,alkyl and cycloalkyl.

In the definition of R⁹ and R¹¹, “—R¹⁰(OR¹⁰)_(w)” refers to a PEG-likechain.

In one embodiment R⁹ and R¹¹ are each the same or different and are eachindependently selected from the group consisting of H, alkyl,cycloalkyl, and —R¹⁰-cycloalkyl, or any subset thereof. Moreparticularly, R⁹ and R¹¹ are each the same or different and are eachindependently selected from the group consisting of H and alkyl.

In one embodiment, R¹⁰ is alkyl or cycloalkyl; more particularly alkyl.

In one class of compounds of formula (I), Y¹ is CH. In anotherembodiment, the compounds of formula (I) are defined wherein Y¹ is N.

When Y¹ is CH. p is 0, 1 or 2 and R⁶ may be bonded through Y¹. When Y¹is N, p is 0 or 1 and R⁶ may not be bonded through Y¹. In oneembodiment, p is 0 or 1. In one particular embodiment, p is 0.

Compounds of formula (I) include those compounds defined wherein R⁶contains an aryl, heterocyclic or heteroaryl moiety. In one embodiment,compounds of the present invention include those compounds definedwherein R⁶ contains a heterocyclic or heteroaryl moiety. Another classof compounds of formula (I) includes those compounds defined wherein R⁶does not contain an aryl, heterocyclic or heteroaryl moiety. Yet anotherclass of compounds include those defined wherein R⁶ does not contain aheterocyclic or heteroaryl moiety but may contain an aryl moiety. Basedon the guidance given above for R¹, one skilled in the art can readilydetermine the list of appropriate groups defining R⁶ which contain orexclude aryl, heterocyclic or heteroaryl moeities.

When Y¹ is CH and p is 2, the two adjacent R⁶ groups (i.e., R⁶ bonded atC-4 and R⁶ bonded at C-5) together with the atoms to which they arebonded may optionally form a C₅₋₆ cycloalkyl or a 5- or 6- memberedheterocyclic group containing 1 or 2 heteroatoms. By “two adjacent R⁶groups” is meant that two R⁶ groups are bonded to adjacent carbon atoms(C-4 and C-5). In the embodiments where two adjacent R⁶ groups togetherwith the atoms to which they are bonded form a C₅₋₆ cycloalkyl or a 5-or 6-membered heterocyclic group containing 1 or 2 heteroatoms, each R⁶group may be the same or different and is preferrably selected from thegroup consisting of alkyl, alkenyl, —OR⁷, —NR⁷R⁸ and —S(O)_(n)R⁹. Forexample, in one embodiment two adjacent R⁶ groups are —OR⁷ and togetherwith the atoms to which they are bonded, they form a heterocyclic groupsuch as:

In another embodiment, two adjacent R⁶ groups are alkyl and togetherwith the atoms to which they are bonded, they form a cycloalkyl groupsuch as:

In another embodiment two adjacent R⁶ groups are defined as —OR⁷ and—NR⁷R⁸ respectively and together with the atoms to which they arebonded, they form a heterocyclic group such as:

From these examples, additional embodiments can be readily ascertainedby those skilled in the art Preferably the compounds of formula (I) aredefined wherein when p is 2, two adjacent R⁶ groups together with theatoms to which they are bonded do not form a C₅₋₆ cycloalkyl or a 5-or-6-membered heterocyclic group containing 1 or 2 heteroatoms.

In one embodiment, R⁶ is the same or different and is independentlyselected from the group consisting of halo, alkyl, Ay, Het, —C(O)Het,—CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —OR⁷, —OAy, —NR⁷R⁸, —NR⁷Ay, —NHHet,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, —R¹⁰OR⁹ and cyano. Moreparticularly, each R⁶ is the same or different and is independentlyselected from the group consisting of halo, alkyl, Het, —OR⁷′, —NR⁷R⁸,—NHHet, —S(O)_(n)R⁹, and cyano, or any subset thereof. In one embodimenteach R⁶ is the same or different and is independently selected from thegroup consisting of halo, alkyl. Het, —NR⁷R⁸, —NHHet and and—S(O)_(n)R⁹.

More specific examples of particular R⁶ groups include but are notlimited to —NH₂, —NHalkyl, —NHR¹⁰OR⁹, —NH-cycloalkyl, and—S(O)_(n)alkyl. In one embodiment, R⁶ is selected from the groupconsisting of —O—butyl, —NH₂,—NHCH(CH₃)₂, —NH-cyclopropyl, —NH-n-propyl,—NH-n-butyl, —NH-cyclopentyl, —NH-cyclohexyl, —NH(CH₂)₂—O—CH₃, —S-methyland —S-ethyl.

In one embodiment, compounds of formula (I) are defined wherein, Y isCH. In another embodiment, the compounds of formula (I) are definedwherein Y is N.

Compounds of formula (I) include those compounds defined wherein R²contains an aryl, heterocyclic or heteroaryl moiety. In one embodiment,compounds of the present invention include those compounds definedwherein R² contains a heterocyclic or heteroaryl moiety. Another classof compounds of formula (I) includes those compounds defined wherein R²does not contain an aryl, heterocyclic or heteroaryl moiety. Yet anotherclass of compounds include those defined wherein R² does not contain aheterocyclic or heteroaryl moiety but may contain an aryl moiety. Basedon the guidance given above for R¹, one skilled in the art can readilydetermine the list of appropriate groups defining R² which contain orexclude aryl, heterocyclic or heteroaryl moeities.

In one embodiment, R² is selected from the group consisting of Ay, Het,—OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)_(n)Ay,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, or any subset thereof. More particularly, R² isselected from the group consisting of Het, —NR⁷R⁸ ₁, —NR⁷Ay, —NHHet,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, or any subset thereof. Particular compounds offormula (I) are defined where R² is selected from the group consistingof Het, —NR⁷R⁸, —NR⁷Ay and —NHHet, or any subset thereof. In oneembodiment, R² is selected from the group consisting of —NR⁷R⁸ 9, —NR⁷Ayand —NHHet, or any subset thereof. In another embodiment, R² is —NR⁷R⁸or —NHHet. In one particular embodiment, R² is —NR⁷R⁸. In oneembodiment, R² is not —NR⁷Ay, more specifically, R² is not NH-phenyl.

More specifically, in one embodiment, R² is selected from the groupconsisting of —NH₂,—NH-alkyl, —NH-cycloalkyl, —N(alkyl)(alkyl),—NH-phenyl, —N(alkyl)-phenyl, Het (e.g., pyrrolidine), —NHHet and—NH-alkyl-Het, or any subset thereof. More particularly, R² is selectedfrom the group consisting of —NH-alkyl, —NH-cycloalkyl and —NH-phenyl,or any subset thereof. In one embodiment, R² is —NH-alkyl or—NH-cycloalkyl.

Specific examples of some particular R² groups are selected from thegroup consisting of —NH₂,—NH-methyl, —NH-ethyl, —N H-propyl,—NH-isopropyl, —NH-cyclopropyl, —NH-butyl, —NH-isobutyl,—NH-cyclopentyl, —NH-cyclohexyl, —NH(CH₂)₂OCH₃, —NH-phenyl,—N(methyl)-phenyl, and pyrrolidine (e.g., pyrrolidine bonded through N).In one embodiment, R² is selected from the group consisting of—NH₂,—NH-methyl, —NH-ethyl, —NH-propyl, —NH-isopropyl, —NH-cyclopropyl,—NH-butyl, —NH-isobutyl, —NH-cyclopentyl, —NH-cyclohexyl, —NH(CH₂)₂OCH₃and pyrrolidine (e.g., pyrrolidine bonded through N).

In another embodiment, the compounds of formula (I) include thosecompounds defined where at least one of R³ and R⁴ contain a heterocyclicor heteroaryl moiety. Another embodiment includes those compounds offormula (I) where neither R³ nor R⁴ contain a heterocyclic or heteroarylmoiety. Based on the guidance given above for R¹, one skilled in the artcan readily determine the list of appropriate groups defining R³ and R⁴which contain or exclude aryl, heterocyclic or heteroaryl moeities.

In one embodiment, R³ is preferably selected from the group consistingof H, halo, alkyl, Ay, —CO₂R⁷, —OR⁷, —NR⁷R⁸, —R¹⁰OR⁷ and —R¹⁰NR⁷R⁸, orany subset thereof. More particularly, R³ is selected from the groupconsisting of H, halo, alkyl, —OR⁷ and —NR⁷R⁸ ₁ or any subset thereof.In one embodiment, R³ is H or alkyl. In one embodiment R³ is H.

In one embodiment, R⁴ is selected from the group consisting of H, halo,alkyl, Ay, —CO₂R⁷, —OR⁷, —NR⁷R⁸, —R¹⁰OR⁷ and —R¹⁰NR⁷R⁸, or any subsetthereof. More particularly R⁴ is selected from the group consisting ofH, halo, alkyl, OR⁷ and —NR⁷R⁸, or any subset thereof. In oneembodiment, R⁴ is H or alkyl. In one embodiment, R⁴ is H.

in formula (I) above is herein referred to as “Ring A.”

Ring A is aryl, a 5–10 membered heterocyclic group or a 5–10 memberedheteroaryl group (including 1, 2, 3 or 4 heteroatoms selected from N, Oand S). Ring A may be bonded to the C-2 carbon of the fused ring throughany available atom including any available heteroatom.

In one embodiment, Ring A is selected from the group consisting of aryl,a 5–6 membered heterocyclic or heteroaryl group and a 9-memberedheterocyclic or heteroaryl group.

In one embodiment, Ring A is selected from the group consisting ofphenyl, naphthyl, furan, pyridine, pyrimidine, thiazole, pyrazine,pyrrole, imidazole, oxazole, benzimidazole, quinoline, isoquinoline, andquinoxoline, or any subset thereof. More particularly, Ring A in formula(I) is selected from the group consisting of phenyl, furan, pyridine andpyrimidine. In one embodiment, Ring A contains at least one N atom andis bonded through N. In another embodiment, Ring A is phenyl.

In one embodiment, q is 0, 1 or 2. In one particular embodiment, q is 0.In one embodiment q is 1.

R⁵ may be bonded to any available carbon or heteroatom of Ring A.Compounds of formula (I) include those compounds defined wherein R⁵contains an aryl, heterocyclic or heteroaryl moiety. In one embodiment,compounds of the present invention include those compounds definedwherein R⁵ contains a heterocyclic or heteroaryl moiety. Another classof compounds of formula (I) includes those compounds defined wherein R⁵does not contain an aryl, heterocyclic or heteroaryl moiety. Yet anotherclass of compounds include those defined wherein R⁵ does not contain aheterocyclic or heteroaryl moiety but may contain an aryl moiety. Basedon the guidance given above for R¹, one skilled in the art can readilydetermine the list of appropriate groups defining R⁵ which contain orexclude aryl, heterocyclic or heteroaryl moeities.

In one embodiment, each R⁵ group is the same or different and isindependently selected from the group consisting of halo, alkyl,alkenyl, Ay, Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —OR⁷, —OAy, —NR⁷R⁸,—NR⁷Ay, —S(O)₂NR⁷R⁸, cyano, nitro and azido, or any subset thereof. Moreparticularly, each R⁵ group is the same or different and isindependently selected from the group consisting of halo, alkyl,alkenyl, —OR⁷, —NR⁷R⁸, Ay, Het, cyano and azido, or any subset thereof.In one embodiment, each R⁵ group is the same or different and isindependently selected from the group consisting of halo, alkyl, —OR⁷,—NR⁷R⁸ and cyano, or any subset thereof. In one embodiment, R⁵ is halo,alkyl or OR⁷.

In particular, specific embodiments of the compounds of formula (I) aredefined where R⁵ is halo (e.g., fluoro, chloro or bromo), alkyl (e.g.,methyl), O-alkyl (e.g., O-methyl, O-isobutyl, and

cyano, —NH—CH₃, and —N(CH₃)₂.

It is to be understood that the present invention includes allcombinations and subsets of the particular and preferred groups definedhereinabove.

Specific compounds of formula (I) include but are not limited to:

-   N—Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4yl]-2-(4-fluorophenyl)pyrazolo-[1,5-c]pyrimidin-7-amine;-   N—Cyclopentyl-3-[2-(cyclopropylamino)pyrimidin-4yl]-2-(4fluorophenyl)pyrazolo-[1,5-c]pyrimidin-7-amine;-   4-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine;-   4-[2-(3-Chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine;-   2-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-amine;-   4-[2-(3-Chlorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentyl-2-pyrimidinamine;-   2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)pyrazolo[1,5-c]pyrimidin-7-amine;-   2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-ol;-   N—Cyclopentyl-8-(2-fluoro-4-pyridinyl)-2-(methylsulfanyl)-7-phenyl    pyrazolo[1,5-a][1,3,5]triazin-4amine;-   N²,N⁴-Dicyclopentyl-8-[2-(cyclopentylamino)-4-pyridinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazine-2,4diamine;    and-   N-Cyclopentyl-8-[2-(cyclopentylamino)-4-pyrimidinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine;-   3-[2-(Butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;-   3-(2-Anilinopyrimidin-4-yl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;-   3-[2-(1,3-Benzothiazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;-   N-Cyclopentyl-2-(4-fluorophenyl)-3-{2-[[4-methyl-1,3-thiazol-2-yl)amino]pyrimidin-4yl}pyrazolo[1,5-c]pyrimidin-7-amine;-   3-[2-(1H-Benzimidazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;-   N-Cyclopentyl-3-{2-[[4-fluorobenzyl)amino]pyrimidin-4-yl}-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;-   N-Cyclopentyl-2-(4-fluorophenyl)-3-{2-[(2-phenylethyl)amino]pyrimidin-4-yl}pyrazolo[1,5-c]pyrimidin-7-amine;-   3-[2-(tert-Butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;-   N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-    c]pyrimidin-3-yl]pyrimidin-2-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-amine;-   4-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-c]pyrimidin-2-yl}phenol;-   3-[2-(Cyclopentylamino)pyrimidin-4-yl]-N-cyclopropyl-2-(4methoxyphenyl)pyrazolo-[1,5-c]pyrimidin-7-amine;-   2-(4-Butoxyphenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-c]pyrimidin-7-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-[4-(2-methoxyethoxy)phenyl]pyrazolo[1,5-c]pyrimidin-7-amine;-   N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-propoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-amine;-   N-(tert-Butyl)-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;-   N-Cyclopentyl-4-[2-(4fluorophenyl)-7-pyrrolidin-1-ylpyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine;    and-   N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-piperidin-1-yl    pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine, or    a pharmaceutically acceptable salt, solvate or physiologically    functional derivative thereof.

It will be appreciated by those skilled in the art that the compounds ofthe present invention may also be utilized in the form of apharmaceutically acceptable salt or solvate thereof. Thepharmaceutically acceptable salts of the compounds of formula (I)include conventional salts formed from pharmaceutically acceptableinorganic or organic acids or bases as well as quaternary ammoniumsalts. More specific examples of suitable acid salts includehydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric,fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic,tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic,naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic,malic, steroic, tannic and the like. Other acids such as oxalic, whilenot in themselves pharmaceutically acceptable, may be useful in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable salts. Morespecific examples of suitable basic salts include sodium, lithium,potassium, magnesium, aluminium, calcium, zinc,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine and procaine-salts.

The term “solvate” as used herein refers to a complex of variablestoichiometry formed by a solute (a compound of formula (I)) and asolvent Solvents, by way of example, include water, methanol, ethanol,or acetic acid.

The term “physiologically functional derivative” as used herein refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide of a compound offormula (I), which upon administration to an animal, particularly amammal, such as a human, is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. See, for example, Burger's Medicinal Chemistry And DrugDiscovery, 5th Edition, Vol 1: Principles And Practice.

Processes for preparing pharmaceutically acceptable salts, solvates andphysiologically functional derivatives of the compounds of formula (I)are conventional in the art. See, e.g., Burger's Medicinal Chemistry AndDrug Discovery 5th Edition, Vol 1: Principles And Practice.

As will be apparent to those skilled in the art, in the processesdescribed below for the preparation of compounds of formula (I), certainintermediates, may be in the form of pharmaceutically acceptable salts,solvates or physiologically functional derivatives of the compound.Those terms as applied to any intermediate employed in the process ofpreparing compounds of formula (I) have the same meanings as noted abovewith respect to compounds of formula (I). Processes for preparingpharmaceutically acceptable salts, solvates and physiologicallyfunctional derivatives of such intermediates are known in the art andare analogous to the process for preparing pharmaceutically acceptablesalts, solvates and physiologically functional derivatives of thecompounds of formula (I).

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The present invention also covers the individualisomers of the compounds represented by formula (I) as mixtures withisomers thereof in which one or more chiral centres are inverted.Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention.

The present invention further provides compounds of formula (I) for usein medical therapy, e.g. in the treatment or prophylaxis, includingsuppression of recurrence of symptoms, of a viral disease in an animal,e.g. a mammal such as a human. The compounds of formula (I) areespecially useful for the treatment or prophylaxis of viral diseasessuch as herpes viral infections. Herpes viral infections include, forexample, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2),cytomegalovirus (CMV), Epstein Barr virus (EBV), Varicella zoster virus(VZV), human herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7), andhuman herpes virus 8 (HHV-8). Thus, the compounds of the invention arealso useful in the treatment or prophylaxis of the symptoms or effectsof herpes virus infections.

The compounds of the invention are useful in the treatment orprophylaxis of conditions or diseases associated with herpes virusinfections, particularly conditions or diseases associated with latentherpes virus infections in an animal, e.g., a mammal such as a human. Byconditions or diseases associated with herpes viral infections is meanta condition or disease, excluding the viral infection per se, whichresults from the presence of the viral infection, such as chronicfatigue syndrome which is associated with EBV infection; and multiplesclerosis which has been associated with herpes viral infections such asEBV and HHV-6. Further examples of such conditions or diseases aredescribed in the background section above.

In addition to those conditions and diseases, the compounds of thepresent invention may also be used for the treatment or prophylaxis ofcardiovascular diseases and conditions associated with herpes virusinfections, in particular atherosclerosis, coronary artery disease andrestenosis and specifically restenosis following angioplasty (RFA).Restenosis is the narrowing of the blood vessels which can occur afterinjury to the vessel wall, for example injury caused by balloonangioplasty or other surgical and/or diagnostic techniques, and ischaracterized by excessive proliferation of smooth muscle cells in thewalls of the blood vessel treated. It is thought that in many patientssuffering from RFA, viral infection, particularly by CMV and/or HHV-6 ofthe patient plays a pivotal role in the proliferation of the smoothmuscle cells in the coronary vessel treated. Restenosis can occurfollowing a number of surgical and/or diagnostic techniques, forexample, transplant surgery, vein grafting, coronary by-pass graftingand, most commonly following angioplasty.

There is evidence from work done both in vitro and in vivo, indicatingthat restenosis is a multifactorial process. Several cytokines andgrowth factors, acting in concert, stimulate the migration andproliferation of vascular smooth muscle cells (SMC) and production ofextracellular matrix material, which accumulate to occlude the bloodvessel. In addition growth suppressors act to inhibit the proliferationof SMC's and production of extracellular matrix material.

In addition, compounds of formula (I) may be useful in the treatment orprophylaxis of conditions or diseases associated with hepatitis B orhepatitis C viruses, human papilloma virus (HPV) and HIV.

Thus, the present invention provides a method for the treatment orprophylaxis of a viral infection in an animal such as a mammal (e.g., ahuman), particularly a herpes viral infection, which method comprisesadministering to the animal a therapeutically effective amount of thecompound of formula (I).

As used herein, the term “prophylaxis” refers to the prevention ofinfection, the prevention of occurrence of symptoms in an infectedsubject, the prevention of recurrence of symptoms in an infectedsubject, or a decrease in severity or frequency of symptoms of viralinfection, condition or disease in the subject

As used herein, the term “treatment” refers to the partial or totalelimination of symptoms or decrease in severity of symptoms of viralinfection, condition or disease in the subject, or the elimination ordecrease of viral presence in the subject. As used herein, the term“therapeutically effective amount” means an amount of a compound offormula (I) which is sufficient, in the subject to which it isadministered, to treat or prevent the stated disease, condition orinfection. For example, a therapeutically effective amount of a compoundof formula (I) for the treatment of a herpes virus infection is anamount sufficient to treat the herpes virus infection in the subject.

The present invention also provides a method for the treatment orprophylaxis of conditions or diseases associated with herpes viralinfections in an animal such as a mammal (e.g., a human), whichcomprises administering to the animal a therapeutically effective amountof the compound of formula (I). In one embodiment, the present inventionprovides a method for the treatment or prophylaxis of chronic fatiguesyndrome or multiple sclerosis in an animal such as a mammal (e.g., ahuman), which comprises administering to the animal a therapeuticallyeffective amount of a compound of formula (I). The foregoing method isparticularly useful for the treatment or prophylaxis of chronic fatiguesyndrome or multiple sclerosis associated with latent infection with aherpes virus.

In another embodiment, the present invention provides a method for thetreatment or prophylaxis of a cardiovascular condition such asatherosclerosis, coronary artery disease or restenosis (particularlyrestenosis following surgery such as angioplasty), which comprisesadministering to the animal a therapeutically effective antiviral amountof the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of hepatitis B or hepatitis C viruses in an animal such as amammal (e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of human papilloma virus in an animal such as a mammal(e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of HIV in an animal such as a mammal (e.g., a human), whichcomprises administering to the animal a therapeutically effective amountof the compound of formula (I).

The present invention also provides the use of the compound of formula(I) in the preparation of a medicament for the treatment or prophylaxisof a viral infection in an animal such as a mammal (e.g., a human),particularly a herpes viral infection; the use of the compound offormula (I) in the preparation of a medicament for the treatment ofconditions or diseases associated with a herpes viral infection; and theuse of the compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of hepatitis B or hepatitis C viruses,human papilloma virus and HIV. In particular, the present invention alsoprovides the use of a compound of formula (I) in the preparation of amedicament for the treatment or prophylaxis of chronic fatigue syndromeor multiple sclerosis. In one embodiment, the present invention providesthe use of a compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of cardiovascular disease, such asrestenosis and atherosclerosis.

The compounds of formula (I) are conveniently administered in the formof pharmaceutical compositions. Such compositions may conveniently bepresented for use in conventional manner in admixture with one or morephysiologically acceptable carriers or diluents

While it is possible that compounds of the present invention may betherapeutically administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation orcomposition. The pharmaceutical composition may comprise apharmaceutically acceptable carrier or diluent. The carrier(s) ordiluent(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

Accordingly, the present invention further provides for a pharmaceuticalformulation or composition comprising a compound of formula (I). In oneembodiment, the pharmaceutical composition further comprises one or morepharmaceutically acceptable carriers or diluents and optionally, othertherapeutic and/or prophylactic ingredients.

The formulations include those suitable for oral, parenteral (includingsubcutaneous e.g. by injection or by depot tablet, intradermal,intrathecal, intramuscular e.g. by depot and intravenous), rectal andtopical (including dermal, buccal and sublingual) administrationalthough the most suitable route may depend upon for example thecondition, age, and disorder of the recipient as well as the viralinfection or disease being treated. The formulations may conveniently bepresented in unit dosage form and may be prepared by any of the methodswell known in the art of pharmacy. All methods include the step ofbringing into association the compound(s) (“active ingredient”) with thecarrier which constitutes one or more accessory ingredients. In generalthe formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation. Formulations suitable for oral administrationmay be presented as discrete units such as capsules (including soft-gelcapsules), cachets or tablets (e.g. chewable tablets in particular forpaediatric administration) each containing a predetermined amount of theactive ingredient; as a powder or granules; as a solution or asuspension in an aqueous liquid or a non-aqueous liquid; or as anoil-in-water liquid emulsion or a water-in-oil liquid emulsion. Theactive ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the- active ingredient in afree-flowing form such as a powder or granules, optionally mixed withother conventional excipients such as binding agents, (for example,syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch orpolyvinylpyrrolidone), fillers (for example, lactose, sugar,microcrystalline cellulose, maize-starch, calcium phosphate orsorbitol), lubricants (for example, magnesium stearate, stearic acid,talc, polyethylene glycol or silica), disintegrants (for example, potatostarch or sodium starch glycollate) or wetting agents, such as sodiumlauryl sulfate. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. The tablets may be coated according to methodswell-known in the art.

Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides. Liquid preparations may also beformulated as soft-gel capsules for oral administration, e.g.,containing conventional soft-gel excipients such as polyethylene glycol.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described. Formulations for rectal administration may bepresented as a suppository with the usual carriers such as cocoa butter,hard fat or polyethylene glycol.

Formulations suitable for topical (e.g., dermal) or intranasalapplication include ointments, creams, lotions, pastes, gels, sprays,aerosols and oils. Suitable carriers for such formulations includepetroleum jelly, lanolin, polyethyleneglycols, alcohols and combinationsthereof.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured base such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a base such as gelatinand glycerin or sucrose and acacia.

The compounds may also be formulated as depot preparations. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavouring agents.

It will be appreciated that the amount of a compound of the inventionrequired for use in treatment will vary with the nature of the conditionbeing treated and the age and the condition of the patient and will beultimately at the discretion of the attendant physician or veterinarian.In general, however, doses employed for adult human treatment willtypically be in the range of 0.02–5000 mg per day, preferably 100–1500mg per day. The desired dose may conveniently be presented in a singledose or as divided doses administered at appropriate intervals, forexample as two, three, four or more sub-doses per day. The formulationsaccording to the invention may contain between 0.1–99% of the activeingredient, conveniently from 30–95% for tablets and capsules and 3–50%for liquid preparations.

The compound of formula (I) for use in the instant invention may be usedin combination with other therapeutic agents for example, non-nucleotidereverse transcriptase inhibitors, nucleoside reverse transcriptaseinhibitors, protease inhibitors and/or other antiviral agents. Theinvention thus provides in a further aspect the use of a combinationcomprising a compound of formula (I) with a further therapeutic agent inthe treatment of viral infections. Particular antiviral agents which maybe combined with the compounds of the present invention includeaciclovir, valaciclovir, fameyclovir, gancyclovir, docosanol, miribavir,amprenavir, lamivudine, zidovudine, and abacavir. Preferred antiviralagents for combining with the compounds of the present invention includeaciclovir and valaciclovir. Thus the present invention provides in afurther aspect, a combination comprising a compound of formula (I) andan antiviral agent selected from the group consisting of aciclovir andvalaciclovir; the use of such combination in the treatment of viralinfections and the preparation of a medicament for the treatment ofviral infections, and a method of treating viral infections comprisingadministering a compound of formula (I) and an antiviral agent selectedfrom the group consisting of aciclovir and valaciclovir.

When a compound of formula (I) is used in combination with othertherapeutic agents, the compounds may be administered eithersequentially or simultaneously by any convenient route.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above optionallytogether with a pharmaceutically acceptable carrier or diluent comprisea further aspect of the invention. The individual components of suchcombinations may be administered either sequentially or simultaneouslyin separate or combined pharmaceutical formulations. When combined inthe same formulation it will be appreciated that the two compounds mustbe stable and compatible with each other and the other components of theformulation and may be formulated for administration. When formulatedseparately they may be provided in any convenient formulation, in such amanner as are known for such compounds in the art.

When a compound of formula (I) is used in combination with a secondtherapeutic agent active against the viral infection, the dose of eachcompound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart.

Compounds of formula (I) wherein Y¹ is N; R¹ is selected from the groupconsisting of Het, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet,—S(O)_(n)R⁹, —S(O)_(n)Ay and —S(O)_(n)Het; p is 1 and R⁶ is —SR⁹, may beprepared by the process outlined in Scheme 1 below.

wherein:

-   -   R¹ is selected from the group consisting of Het, —OR⁷, —OAy,        —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)_(n)Ay and        —S(O)_(n)Het;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰Ay, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹,        —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰SO₂R¹⁰ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;

-   Y¹ is N;

-   p is 1;

-   R⁶ is —SR⁹;

-   Y is N or CH;

-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷ ₁, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay,    —NHHet —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, alkenyl,    cycloalkyl, Ay, Het, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, OR⁷, —OAy,    —NR⁷R⁸, —NR⁷Ay, —NHHet, —SO₂NHR⁹, —R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy,    —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;

-   Ring A is selected from the group consisting of aryl, 5–10 membered    heterocyclic group and a 5–10 membered heteroaryl group;

-   q is 0, 1, 2, 3, 4 or 5; and

-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O) Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,—C(NH)NR⁷Ay, —OR⁷,    —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,    —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, cyano, nitro and azido;

-   X is chloro, bromo or iodo;

-   X¹ is chloro, bromo, or iodo; and

-   M¹ is —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, or    Mg-halide where Ra is alkyl or cycloalkyl and halide is halo.

Generally, the process for preparing the compounds of formula (I)wherein Y¹ is N; R¹ is selected from the group consisting of Het, —OR⁷,—OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)_(n)Ay and—S(O)_(n)Het; p is 1 and R⁶ is —SR⁹, (all formulas and all othervariables having been defined above in connection with Scheme 1)comprises the steps of:

-   (a) reacting a compound of formula (II) with an isothiocyanate of    formula (III) to prepare a compound of formula (IV);-   (b) reacting the compound of formula (IV) with a base to prepare a    compound of formula (V);-   (c) reacting the compound of formula (V) with a base and an    alkylating agent to prepare a compound of formula (VI);-   (d) reacting a compound of formula (VI) with phosphorous oxychloride    to prepare a compound of formula (VII);-   (e) reacting a compound of formula (VII) with a heteroatom (N,O,S)    nucleophile to prepare a compound of formula (VIII);-   (f) halogenating a compound of formula (VIII) to prepare a compound    of formula (IX); and-   (g) reacting a compound of formula (IX) with a compound of    formula (X) to prepare a compound of formula (I).

More specifically, compounds of formula (I) wherein Y¹ is N; R¹ isselected from the group consisting of Het, —OR⁷, —OAy, —OHet, —NR⁷R⁸,—NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)_(n)Ay and —S(O)_(n)Het; p is 1 and R⁶is —SR⁹, can be prepared by reacting a compound of formula (IX) with acompound of formula (X).

wherein all variables are as defined above in connection with Scheme 1.

The reaction may be carried out in an inert solvent, in the presence ofa palladium (O) or nickel (O) catalyst. The reaction may optionally beheated to about 50–150° C. Typically the reaction is performed byreacting equimolar amounts of a compound of formula (IX) with aheteroaryl-metal compound of formula (X), but the reaction may also beperformed in the presence of an excess of compound of the formula (X).The palladium or nickel catalyst is typically present in 1–10 mol %compared to the compound of formula (IX). Examples of suitable palladiumcatalysts include but are not limited to,tetrakis(triphenylphosphine)palladium (O),dichlorobis(triphenyl-phosphine)palladium(II),tris(dibenzylideneacetone)dipalladium (O), andbis(diphenylphosphinoferrocene)palladium (II) dichloride. Suitablesolvents include but are not limited to, N,N-dimethylformamide, toluene,tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone. When theheteroaryl-metal compound of formula (X) is an arylboronic acid or esteror an arylborinate the reaction is more conveniently carried out byadding a base in a proportion equivalent to, or greater than, that ofthe compound of formula (X). Heteroaryl-metal compounds of formula (X)may be obtained from commercial sources or prepared either as discreetisolated compounds or generated in situ using methods known to oneskilled in the art. (Suzuki, A. J. Organomet. Chem. 1999, 576, 147;Stille, J. Angew. Chem. Int. Ed. Engl. 1986, 25, 508; Snieckus, V. J.Org. Chem. 1995, 60, 292.)

A compound of formula (IX) can be prepared from a compound of formula(VIII) by a halogenation procedure.

wherein all variables are as defined above in connection with Scheme 1.

Typically, the halogenation reaction is carried out by subjecting thecompound of formula (VIII) to a halogenating reagent in a suitablesolvent. Suitable halogenating reagents include but are not limited to,N-bromosuccinimide, trialkylammonium tribromides, bromine,N-chlorosuccinimide, N-iodosuccinimide, iodine, iodine monochloride, andthe like. Suitable solvents include, for example, N,N-dimethylformamide,tetrahydrofuran, dioxane, 1-methyl-2-pyrrolidinone, carbontetrachloride, toluene, dichloromethane, diethyl ether, and the like.

A compound of the formula (VIII) can be prepared from a compound offormula (VII) through reaction with a heteroatom (i.e., N, O or S)nucleophile selected from the group consisting of Het, —OR⁷, —OAy,—OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)_(n)Ay and—S(O)_(n)Het.

wherein all variables are as defined above in connection with Scheme 1.

Typically the chloro compound of formula (VII) can be treated with thenucleophile in an inert solvent or the nucleophile when suitable can beused as the solvent. By way of example some suitable solvents includebut are not limited to 1-methyl-2-pyrrolidinone, N,N-dimethylformamide,tetrahydrofuran, dimethyl sulfoxide, and the lower alcohols such asmethanol, ethanol, isopropanol and the like. The reaction may beperformed at or below ambient temperature or if deemed necessary thereaction may require heating to 50–200° C.

A compound of formula (VII) can be conveniently prepared from a compoundof formula (VI) by treatment with phosphorous oxychloride.

wherein all variables are as defined above in connection with Scheme 1.

Conveniently, this type of transformation can be carried out usingphosphorous oxychloride, optionally in the presence of a base. This isperformed by treating a compound of formula (VI) with phosphorousoxychloride with optional heating. Typically an excess of thedehydrating reagent is used and the reaction can be heated up to refluxtemperature of approximately 105° C. By way of example a suitable baseis N,N-diethylaniline and the like.

A compound of the formula (VI) can be conveniently synthesized from acompound of formula (V) by an alkylation protocol.

wherein all variables are as defined above in connection with Scheme 1.

This sequence can be carried out by reacting a compound of formula (V)with a base and an alkyl halide electrophile in an inert solvent at roomtemperature or optionally with heating. A typical base is aqueous sodiumhydroxide or the like. Other bases can be used under anhydrousconditions such as potassium carbonate, sodium ethoxide, sodium hydrideand the like. Electrophiles include but are not limited to alkyl halidessuch as methyl iodide (R⁹=methyl) and alkyl sulfates such as dimethylsulfate, and the like. A typical solvent system is ethanol/water, butother solvents, with or without an aqueous co-solvent, can be used,including 1-methyl-2-pyrrolidinone, N,N-dimethylformamide,tetrahydrofuran, dimethyl sulfoxide, and the lower alcohols such asmethanol, ethanol, isopropanol, and the like. The reaction canoptionally be heated to 50–200° C.

A compound of formula (V) can be prepared by an intramolecularcondensation ring closing reaction of a compound of formula (IV).

wherein all variables are as defined above in connection with Scheme 1.

This condensation can be typically carried out by treating a compound offormula (IV) with a base in an inert solvent. Typical bases include butare not limited to sodium hydroxide, sodium ethoxide, potassiumcarbonate, potassium tert-butoxide, and the like. Solvents includewater, the lower alcohols such as ethanol, iospropanol, and the like.Additionally solvents can be chosen from1-methyl-2-pyrrolidinone,N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and thelike.

A compound of the formula (IV) can be conveniently formed by reaction ofa compound of formula (II) with an isothiocyanate of formula (III).

wherein all variables are as defined above in connection with Scheme 1.

This can be carried out by reacting a compound of formula (II) with acommercially available isothiocyanate such as ethoxycarbonylisothiocyanate in a inert solvent optionally with heating. A suitablesolvent includes but is not limited to toluene. The reaction may beheated to a temperature of from about 30–150° C.

Compounds of the formula (II) can be purchased from commercial sourcesor prepared using conventional techniques known to one skilled in theart.

In a further embodiment of the present invention, a compound of formula(I) wherein Y¹ is N; R¹ is selected from the group consisting of of Het,—OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay and —NHHet and p is 0, may beconveniently prepared by the process outlined in Scheme 2 below.

wherein:

-   R¹ is selected from the group consisting of Het, —OR⁷, —OAy, —OHet,    —NR⁷R⁸, —NR⁷Ay and —NHHet;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰Ay, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹,        —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰SO₂R¹⁰ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR ¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl, and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y¹ is N;-   p is 0;-   Y is N or CH;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het,—OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay,    —NHHet —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, alkenyl,    cycloalkyl, Ay, Het, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy,    —NR⁷R⁸, —NR⁷Ay, —NHHet, —SO₂NHR⁹, —R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy,    —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   Ring A is selected from the group consisting of aryl, 5–10 membered    heterocyclic group and a 5–10 membered heteroaryl group;-   q is 0, 1, 2, 3, 4 or 5; and-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷,    —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,    —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸ ₁, —R¹⁰NR⁷Ay, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, cyano, nitro and azido;-   X¹ is chloro, bromo, or iodo; and-   M¹ is —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, or    Mg-halide where Ra is alkyl or cycloalkyl and halide is halo.

Generally, the process for preparing a compound of formula (I) whereinY¹ is N; R¹ is selected from the group consisting of of Het, —OR⁷, —OAy,—OHet, —NR⁷R⁸, —NR⁷Ay and —NHHet and p is 0 (all formulas and all othervariables having been defined above in connection with Scheme 2)comprises the steps of:

-   a) reducing a compound of formula (VIII) to prepare a compound of    formula (XI);-   b) halogenating the compound of formula (XI) to prepare a compound    of formula (XII); and-   c) reacting a compound of formula (XII) with a compound of    formula (X) to prepare a compound of formula (I).

More specifically, a compound of formula (I) wherein Y¹ is N; R¹ isselected from the group consisting of of Het, —OR⁷, —OAy, —OHet, —NR⁷R⁸,—NR⁷Ay and —NHHet and p is 0, can be prepared by reacting a compound offormula (XII) with a compound of formula (X).

wherein all variables are as defined above in connection with Scheme 1.

This reaction may be carried out using the same procedures as describedabove in connection with Scheme 1, for the conversion of a compound offormula (IX) to a compound of formula (I).

A compound of formula (XII) can be prepared from a compound of formula(XI) by a halogenation procedure.

wherein all variables are as defined above in connection with Scheme 1.

Typically, the halogenation reaction is carried out by subjecting thecompound of formula (XI) to a halogenating agent in a suitable solvent.Suitable halogenating agents include but are not limited to,N-bromosuccinimide, trialkylammonium tribromides, bromine,N-chlorosuccinimide, N-iodosuccinimide, iodine, iodine monochloride, andthe like. Suitable solvents include, for example, N,N-dimethylformamide,tetrahydrofuran, dioxane, 1-methyl-2-pyrrolidinone, carbontetrachloride, toluene, dichloromethane, diethyl ether, and the like.

A compound of formula (XI) can be conveniently prepared by reduction ofa compound of formula (VIII).

wherein all variables are as defined above in connection with Scheme 1

This method can be carried out by treating a compound of formula (VIII)with Raney-nickel in an alcohol solvent. A preferred solvent is ethanol.The reaction may optionally require heating to 50–150° C. Preparation ofa compound of formula (VIII) is described in connection with Scheme 1above.

In a further embodiment of the present invention, a compound of formula(I) wherein Y¹ is CH; Y is N; R² is selected from the group consistingof alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet—NR⁷R₈, —NR⁷Ay, —NHHet —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay; and R³ and R⁴ are H, may be conveniently prepared by theprocess outlined in Scheme 3 below.

wherein

-   R¹ is selected from the group consisting of H, halo, alkyl, alkenyl,    alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay,    —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹,    —R¹⁰C(O)R⁹ ₁, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O) Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and    azido;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰Ay, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹,        —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰SO₂R¹⁰ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl, and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   p is 0, 1 or 2 when Y¹ is CH,-   p is 0 or 1 when Y¹ is N;-   each R⁶ is the same or different and is independently selected from    the group consisting of H, halo, alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het,    —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹,    —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and    azido; or when p is 2, two adjacent R⁶ groups together with the    carbon atoms to which they are bonded form a cycloalkyl or a 5- or    6-membered heterocyclic group containing 1 or 2 heteroatoms;-   Y is N;-   R² is selected from the group consisting of alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay,    —NHHet —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   R³ and R⁴ are both H-   Ring A is selected from the group consisting of aryl, 5–10 membered    heterocyclic group and a 5–10 membered heteroaryl group;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,—C(NH)NR⁷Ay, —OR⁷,    —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,    —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, cyano, nitro and azido; and-   Ra is alkyl or cycloalkyl.

Generally, the process for preparing a compound of formula (I) whereinY¹ is CH; Y is N; R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸,—NR⁷Ay, —NHHet —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³and R⁴ are H (all formulas and all other variables having been definedabove in connection with Scheme 3), comprises the steps of:

-   (a) reacting a 4-methylpyrimidine of formula (XIV) with an ester of    formula (XIII) to prepare a compound of formula (XV);-   (b) reacting the compound of formula (XV) with a hydroxylamine    source to prepare a compound of formula (XVI);-   (c) reacting the compound of formula (XVI) with an acylating or    sulfonylating agent to prepare a compound of formula (XVII);-   (d) rearranging the compound of formula (XVII) to prepare a compound    of formula (XVIII);-   (e) acylating the compound of formula (XVIII) to prepare a compound    of formula (XIX);-   (f) reacting the compound of formula (XIX) with a dimethylformamide    dialkyl acetal of formula (CH₃)₂NCH(ORa)₂ to prepare a compound of    formula (XX); and-   (g) reacting the compound of formula (XX) with a compound of    formula (XXI) to prepare a compound of formula (I).

More specifically, a compound of formula (I) wherein wherein Y¹ is CH; Yis N; R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NHHet—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R³ and R⁴ are H,can be prepared by reacting a compound of formula (XX) with a compoundof formula (XXI).

wherein all variables are as defined above in connection with Scheme 3.

This method can be readily carried out by mixing a compound of formula(XX) with a compound of formula (XXI) in a suitable solvent, optionallyin the presence of a base (preferably when the amidine is in a saltform), and heating the reaction to 50–150° C. Typical solvents includelower alcohols such as methanol, ethanol, isopropanol andN,N-dimethylformamide or the like. The base is typically a sodiumalkoxide, potassium carbonate, or an amine base such as triethylamine.In one embodiment, the solvent is N,N-dimethylformamide and the base ispotassium carbonate, or an amine base such as triethylamine.

A compound of formula (XX) may be conveniently prepared by reacting acompound of formula (XIX) with a dimethylformamide dialkyl acetal.

wherein all variables are as defined above in connection with Scheme 3.

Typical dimethylformamide dialkylacetal compounds for use in this methodinclude but are not limited to dimethylformamide dimethylacetal anddimethylformamide di-tert-butylacetal. The reaction is carried out bymixing a -compound of formula (XIX) with the dimethylformamide dialkylacetal, optionally with heating.

The foregoing procedure for the conversion of a compound of formula(XIX) to a compound of formula (I) can also be used for the conversionof a compound of formula (VIII) to a compound of formula (I) if desired.

A compound of formula (XIX) may be conveniently prepared from a compoundof formula (XVIII) using an acylation procedure.

wherein all variables are as defined above in connection with Scheme 3.

Typically the acylation is carried out by treating a compound of formula(XVIII) with an acylating agent, optionally in the presence of an acidor Lewis acid catalyst in an inert solvent with optional heating.Typical acylating agents will be readily determined by those skilled inthe art. One preferred acylating agent is acetic anhydride. Lewis acidcatalysts are also known to those skilled in the art. One preferredLewis acid catalyst for use in this reaction is boron trifluoridediethyl etherate. A suitable solvent is toluene. Another preferredreaction condition is catalytic sulfuric acid optionally in acetonitrileand optionally with heating.

A compound of formula (XVIII) can be conveniently prepared byrearranging an azirine compound of formula (XVII).

wherein all variables are as defined above in connection with Scheme 3.

The rearrangement of the azirine of formula (XVII) can be accomplishedby heating a solution of the azirine of formula (XVII) in a suitablesolvent at a temperature of about 160–200° C. Suitable inert solventsinclude, but are not limited to, 1-methyl-2-pyrrolidinone and1,2,4-trichlorobenzene. A more preferred method for rearrangement of theazirine of formula (XVII) to a compound of formula (XVIII) involvesreacting the compound of formula (XVII) with ferrous chloride (FeCl₂) orferric chloride (FeCl₃). See, PCT Publication No. WO 01/83479, published8 Nov. 2001 to GlaxoSmithKline Inc. This reaction is typically done inan inert solvent with heating. A preferred solvent for this reaction is1,2-dimethoxyethane, or the like.

Typically the azirine of formula (XVII) can be prepared from an oximecompound of formula (XVI) by treatment with an acylating orsulfonylating agent in the presence of a base.

wherein all variables are as defined above in connection with Scheme 3.

Typical acylating or sulfonylating agents include but are not limitedto, acetic anhydride, trifluoroacetic anhydride, methanesulfonylchloride, toluenesulfonyl chloride and the like. Typical bases include,but are not limited to, triethylamine, diisopropylethylamine, pyridine,and the like. The reaction may be carried out in an inert solvent suchas for example, chloroform, dichloromethane, toluene or the like.

The oxime compounds of formula (XVI) are readily prepared by treatingketone compounds of formula (XV) with a hydroxylamine source, in asuitable solvent, and optionally with a base.

wherein all variables are as defined above in connection with Scheme 3.

Typically, the hydroxylamine is hydroxylamine hydrochloride and the baseis an aqueous solution of sodium hydroxide. Suitable solvents includelower alcohols such as methanol, ethanol, or isopropanol.

The ketone compounds of formula (XV) can be prepared by treatment of amethylpyrimidine of formula (XIV) with an ester of formula (XIII) in thepresence of a base.

wherein all variables are as defined above in connection with Scheme 3.

An example of a suitable base is lithium bis(trimethylsilyl)amide in aninert solvent such as tetrahydrofuran. Ketones such as those of formula(III) can be readily prepared using procedures known to one skilled inthe art and/or described in the literature (Cassity, R. P.; Taylor, LT.; Wolfe, J. F. J.Org. Chem. 1978, 2286).

In a further embodiment of the present invention, a compound of formula(I) wherein Y is N; R² is selected from the group consisting of alkyl,cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸,—NR⁷Ay, —NHHet —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ isselected from the group consisting of H, alkyl, alkenyl, cycloalkyl, Ay,Het, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy, —NR⁷R⁸ (where R⁷ andR⁸ are not H), —NR⁷Ay (where R⁷ is H), —SO₂NHR⁹, —R¹⁰OR⁷,—R¹⁰cycloalkyl, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R⁴ is H, may beconveniently prepared by the process outlined in Scheme 4 below.

wherein:

-   R¹ is selected from the group consisting of H, halo, alkyl, alkenyl,    alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay,    —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹,    —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and    azido;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(N H)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰Ay, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹,        —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰SO₂R¹⁰ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl, and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y¹ is N or CH;-   p is 0, 1 or 2 when Y¹ is CH,-   p is 0 or 1 when Y¹ is N;-   each R⁶ is the same or different and is independently selected from    the group consisting of H, halo, alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het,    —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹,    —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and    azido; or when p is 2, two adjacent R⁶ groups together with the    carbon atoms to which they are bonded form a cycloalkyl or a 5- or    6-membered heterocyclic group containing 1 or 2 heteroatoms;-   Y is N;-   R² is selected from the group consisting of alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay,    —NHHet —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   R³ is selected from the group consisting of H, alkyl, alkenyl,    cycloalkyl, Ay, Het, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy,    —NR⁷R⁸ (where R⁷ and R⁸ are not H), —NR⁷Ay (where R⁷ is H),    —SO₂NHR⁹, —R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   R⁴ is H;-   Ring A is selected from the group consisting of aryl, 5–10 membered    heterocyclic group and a 5–10 membered heteroaryl group;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷,    —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,    —R¹⁰C(O)NR⁹R¹¹, —R¹⁰OC(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, cyano, nitro and azido; and-   M² is Li, Mg-halide or cerium-halide.

Generally, the process for preparing a compound of formula (I) wherein Yis N; R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NHHet—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected fromthe group consisting of H, alkyl, alkenyl, cycloalkyl, Ay, Het, —C(O)R⁷,C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy, —NR⁷R⁸ (where R⁷ and R⁸ are not H),—NR⁷Ay (where R⁷ is H), —SO₂NHR⁹, —R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R⁴ is H, comprises the following steps:

-   (a) formylating a compound of formula (XVIII-A) to prepare a    compound of formula (XXII);-   (b) reacting the compound of formula (XXII) with a compound of    formula (XXIII) to prepare a compound of formula (XXIV);-   (c) oxidizing the compound of formula (XXIV) to prepare a compound    of formula (XXV); and-   (d) reacting the compound of formula (XXV) with a compound of    formula (XXI) to prepare the compound of formula (I).

More specifically, a compound of formula (I) wherein Y is N; R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NHHet—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected fromthe group consisting of H, alkyl, alkenyl, cycloalkyl, Ay, Het, —C(O)R⁷,C(O)Ay, —CO₂R⁷ ₁, —CO₂Ay, —OR⁷, —OAy, —NR⁷R⁸ (where R⁷ and R⁸ are notH), —NR⁷Ay (where R⁷ is H), —SO₂NHR⁹, —R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R⁴ is H, may be prepared by reacting acompound of formula (XXV) with a compound of formula (XXI).

wherein all variables are as defined above in connection with Scheme 4.

This method can be readily carried out by mixing a compound of formula(XXV) with a compound of formula (XXI) in a suitable solvent, optionallyin the presence of a base. The reaction may be heated to 50–150° C. orperformed at ambient temperature. Typical solvents include but are notlimited to lower alcohols such as methanol, ethanol, isopropanol and thelike. Typical bases include for example, sodium alkoxide, potassiumcarbonate, or an amine base such as triethylamine. In anotherembodiment, the solvent is N,N-dimethylformamide and the base ispotassium carbonate, or an amine base such as triethylamine.

A compound of formula (XXV) may be conveniently prepared by oxidation ofa compound of formula (XXIV).

wherein all variables are as defined above in connection with Scheme 4.

Typical oxidizing agents include but are not limited to, manganesedioxide, and the like, in an inert solvent Suitable inert solventsinclude but are not limited to, dichloromethane, chloroform,N,N-dimethylformamide, ether, and the like.

A compound of formula (XXIV) may be conveniently prepared by reacting acompound of formula (XXII) with a compound of formula (XXIII).

wherein all variables are as defined above in connection with Scheme 4.

Suitable metals (M²) in the compounds of formula (XXIII) include but arenot limited to, lithium, magnesium(II) halides, cerium(III) halides, andthe like. A compound of formula (XXIII) may be purchased from commercialsources or prepared by methods known to one skilled in the art.

A compound of formula (XXII) may be conveniently prepared from acompound of formula (XVIII-A) by a formulation procedure.

wherein all variables are as defined above in connection with Scheme 4.

Typically the formylation is carried out via the Vilsmeier-Haackreaction. The Vilsmeier-Haack reagents can be purchased from commercialsources or prepared in situ. Typical conditions include, but are notlimited to treating a compound of formula (XVIII) with a premixedsolution of phosphorous oxychloride in N,N-dimethylformamide optionallywith heating the reaction to about 50–150° C. The compounds of formula(XVIII-A) may be prepared according to the process described in previousSchemes.

A compound of formula (I) wherein Y is N; and R² is selected from thegroup consisting of alkyl cycloalkyl, alkenyl, cycloalkenyl, Ay, Het,—OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NHHet —S(O)_(n)R⁹, —S(O)_(n)Ay,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, may be conveniently prepared by the processoutlined in Scheme 5 below.

wherein:

-   R¹ is selected from the group consisting of H, halo, alkyl, alkenyl,    alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay,    —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R₈,    —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹;    S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹,    —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰C(O)Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and    azido;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰Ay, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹,        —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(N H)NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰SO₂R¹⁰ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl, and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y¹ is N or CH;-   p is 0, 1 or 2 when Y¹ is CH,-   p is 0 or 1 when Y¹ is N;-   each R⁶ is the same or different and is independently selected from    the group consisting of H, halo, alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het,    —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹,    —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and    azido; or when p is 2, two adjacent R⁶ groups together with the    carbon atoms to which they are bonded form a cycloalkyl or a 5- or    6-membered heterocyclic group containing 1 or 2 heteroatoms;-   Y is N;-   R² is selected from the group consisting of alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay,    —NHHet —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, alkenyl,    cycloalkyl, Ay, Het, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy,    —NR⁷R⁸, —NR⁷Ay, —NHHet, —SO₂NHR⁹, —R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy,    —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   Ring A is selected from the group consisting of aryl, 5–10 membered    heterocyclic group and a 5–10 membered heteroaryl group;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷,    —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,    —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay , —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, cyano, nitro and azido; and-   M² is Li, Mg-halide or cerium-halide, wherein halide is halo.

Generally, the process for preparing a compound of formula (I) wherein Yis N and R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NHHet—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, comprises thefollowing steps:

-   (a) reacting a compound of formula (XXII) with a compound of    formula (XXVI) to prepare a compound of formula (XXVII);-   (b) oxidizing the compound of formula (XXVII) to prepare a compound    of formula (XXVIII); and-   c) reacting a compound of formula (XXVIII) with a compound of    formula (XXI) followed by oxidative aromatization to prepare a    compound of formula (I).

More specifically, a compound of formula (I) wherein Y is N and R² isselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NHHet—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, can be prepared byreacting a compound of formula (XXVIII) with a compound of formula (XXI)followed by oxidative aromatization.

wherein all variables are as defined above in connection with Scheme 5.

The condensation is conveniently carried out by treating the compound offormula (XXVIII) with a compound of formula (XXI) in an inert solvent,optionally in the presence of a base. The reaction may be heated toabout 50–150° C. or performed at ambient temperature. Suitable inertsolvents include lower alcohols such as, for example, methanol, ethanol,isopropanol and the like. The base is typically a sodium alkoxide,potassium carbonate, or an amine base such as triethylamine. In anotherembodiment, the solvent is N,N-dimethylformamide and the base ispotassium carbonate, or an amine base such as triethylamine. Thereaction produces a dihydropyrimidine intermediate.

Conveniently in the same reaction vessel, the dihydropyrimidineintermediate may be oxidized to a compound of formula (I) by theaddition of an oxidizing agent The reaction may be heated to 50–150° C.or performed at ambient temperature. Typically, the oxidizing agent isoxygen (O₂), palladium on carbon,2,3-dichloro-5,6-dicyano-1,4-benzoquinone, or the like.

A compound of formula (XXVIII) may be conveniently prepared by oxidationof a compound of formula (XXVII).

wherein all variables are as defined above in connection with Scheme 5.

Typical oxidizing agents for the oxidation of a compound of formula(XXVII) include but are not limited to manganese dioxide, and the like.The oxidation is typically carried out in an inert solvent such as forexample, dichloromethane, chloroform, N,N-dimethylformamide, ether, andthe like.

A compound of formula (XXVII) may be conveniently prepared by reacting acompound of formula (XXII) with a compound of formula (XXVI).

wherein all variables are as defined above in connection with Scheme 5.

A compound of formula (XXVI) may be purchased from commercial sources orprepared by methods known to one skilled in the art. A compound offormula (XXII) may be prepared using the methods described in connectionwith Schemes 3 and 4 above.

In a further embodiment of the invention, a compound of formula (I), maybe conveniently prepared by the process outlined in Scheme 6 below.

wherein

-   R¹ is selected from the group consisting of H, halo, alkyl, alkenyl,    alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay,    —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹,    —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and    azido;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁹R¹¹,        —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹, —R¹⁰cycloalkyl,        —R¹⁰Ay, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,        —R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹,        —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰SO₂R¹⁰ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl, and alkynyl;    -   n is 0, 1 or 2;    -   Ay is aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;-   Y¹ is N or CH;-   p is 0, 1 or 2 when Y¹ is CH,-   p is 0 or 1 when Y¹ is N;-   each R⁶ is the same or different and is independently selected from    the group consisting of H, halo, alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het,    —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,    —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹,    —S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,    —R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹,    —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay,    —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and    azido; or when p is 2, two adjacent R⁶ groups together with the    carbon atoms to which they are bonded form a cycloalkyl or a 5- or    6-membered heterocyclic group containing 1 or 2 heteroatoms;-   Y is N or CH;-   R² is selected from the group consisting of halo, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay,    —NHHet —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, alkenyl,    cycloalkyl, Ay, Het, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy,    —NR⁷R⁸, —NR⁷Ay, —NHHet, —SO₂NHR⁹, —R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy,    —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay;-   Ring A is selected from the group consisting of aryl, 5–10 membered    heterocyclic group and a 5–10 membered heteroaryl group;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷,    —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸,    —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹,    —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰SO₂R⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹, cyano, nitro and azido;-   X¹ is chloro, bromo, or iodo; and-   M¹ is —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, or    Mg-halide where Ra is alkyl or cycloalkyl and halide is halo.

Generally, the process for preparing a compound of formula (I) (allformulas and variables having been defined above in connection withScheme 6), comprises the following steps:

-   a) halogenating a compound of formula (XXIX) to prepare a compound    of formula (XXX); and-   b) reacting the compound of formula (XXX) with a compound of    formula (X) to prepare a compound of formula (I).

More specifically, this sequence of reactions may be carried out in ananalogous manner as described above in connection with Scheme 2. Itshould be noted that a compound of formula (XXX) is in fact the same asa compound of formula (XII) described in Scheme 2 when Y¹ is N and R⁶ isH. It should also be noted that a compound of formula (XXIX) is in factthe same as a compound of formula (XI) when Y¹ is N and p is 0, and thesame as a compound of formula (XVIII) when Y¹ is defined as CH. Acompound of the formula (XXIX) can be prepared using the methodsdescribed above in connection with Schemes 1–4 using techniques known tothose in the art.

In each of the foregoing synthetic processes, the steps are described ina specific order. However, one skilled in the art will readilyappreciate that various steps within each of the reaction schemes may beconducted in a different order. Hence, the order in which the steps ofthe process are performed is not critical to the invention. The presentinvention contemplates and includes analogous processes wherein theorder of the steps differs from the specific embodiment describedherein.

As will be apparent to those skilled in the art, a compound of formula(I) may be converted to another compound of formula (I) using techniqueswell known in the art, i.e., a particular compound of formula (I) may beused as an intermediate in processes for preparing other compounds offormula (I). For example, one method of converting a compound of formula(I) to another compound of formula (I) comprises the steps of:

-   a) oxidizing a compound of formula (I-A) to prepare a compound of    formula (I-B); and-   b) optionally reacting a compound of formula (I-B) with an oxygen or    amine nucleophile of formula R², wherein R² is selected from the    group consisting of —NR⁷R⁸, —OR⁷, Het attached through N, —NHHet,    NHR¹⁰Het, OHet and —OR¹⁰Het to prepare a compound of formula (I)    wherein R² is selected from the group consisting of Het attached    through N, —OR⁷, —OHet, —NR⁷R⁸ and —NHHet.

wherein n′ is 1 or 2;

-   R² is selected from the group consisting of Het attached through N,    —OR⁷, —OHet, —NR⁷R⁸ and —NHHet, all other variables are as defined    according to any process described above.

More specifically, a compound of formula (I) wherein R² is selected fromthe group consisting of Het attached through N, —OR⁷, —OHet, —NR⁷R⁸ and—NHHet; can be prepared by reacting a compound of formula (I-B) (i.e., acompound of formula (I) wherein R² is S(O)_(n)R⁹ where n′ is 1 or 2,with an oxygen or amine nucleophile of formula R², wherein R² isselected from the group consisting of Het attached through N, —OR⁷,—OHet, —NR⁷R⁸ and —NHHet. The reaction may be carried out neat or in asuitable solvent and may be heated to about 50–150° C. Typically thesolvent is a lower alcohol such as methanol, ethanol, isopropanol andthe like or solvent such as N,N-dimethylformamide or tetrahydrofuran,and the like. Optionally a base may be used to facilitate the reaction.Typically the base can be potassium carbonate, or an amine base such astriethylamine.

A compound of formula (I-B) may be conveniently prepared by reacting acompound of formula (I-A) (i.e., a compound of formula (I) wherein R²is: —S(O)_(n)R⁹ where n is 0) with an oxidizing agent in an inertsolvent, optionally in the presence of a base. Typically the oxidizingagent is a peracid such as 3-chloroperbenzoic acid or the likeoptionally with a base such as sodium bicarbonate. Careful monitoring ofthe stoichiometry between the oxidizing agent and the substrate allowsthe product distribution between sulfoxide (n=1), and sulfone (n=2) tobe controlled. Suitable solvents include but are not limited to,dichloromethane, chloroform and the like. If the compound of formula(I-A) contains oxidizeable nitrogens, it may be preferred to perform theoxidation under acidic conditions. Acetic acid, or other suitable acidsknown to those skilled in the art can be added to make the solutionacidic.

Compounds of formula (I-A) are prepared by methods described above inSchemes 1 through 6 wherein R²=SR⁹.

In an analogus procedure, a compound of formula (I) wherein at least oneR⁶ is —SR⁹, may be converted to another compound of formula (I) whereinat least one R⁶ is selected from the group consisting Het attachedthrough N, —OR⁷, —OHet —NR⁷R⁸ and —NHHet. The process comprises thesteps of: a) oxidizing a compound of formula (I-AA) to prepare acompound of formula (I-BB); and b) optionally reacting a compound offormula (I-BB) with an oxygen or amine nucleophile of formula R⁶,wherein R⁶ is selected from the group consisting of Het attached throughN, —OR⁷, —OHet —NR⁷R⁸ and —NHHet to prepare a compound of formula Iwherein at least one R⁶ is selected from the group consisting Hetattached through N, —OR⁷, —OHet —NR⁷R⁸ and —NHHet.

wherein p′ is 0 when Y¹ is N or p′ is 0 or 1 when Y¹ is CH;

-   at least one R⁶ is selected from the group consisting of Het    attached through N, —OR⁷, —OHet —NR⁷R⁸ and —NHHet; and-   all other variables are as defined according to any process    described above.

Compounds of formula (I-AA) are prepared by methods described above inSchemes 1 through 6 wherein at least one R⁶=SR⁹.

Another particularly useful method for converting a compound of formula(I) to another compound of formula (I) comprises reacting a compound offormula (I-C) (i.e., a compound of formula (I) wherein R² is fluoro)with an amine, and optionally heating the mixture to about 50–150° C. toprepare a compound of formula (I-D) (i.e., a compound of formula (I)wherein R² is Het bonded through N, —NR⁷R⁸, —NR⁷Ay and —NHHet).

wherein all other variables are as defined in any process describedabove.

This procedure may be carried out by mixing a compound of formula (I-C)in a neat amine (i.e., R²), or in a suitable solvent with an excess ofan amine to produce a compound of formula (I-D). Typically the solventis a lower alcohol such as methanol, ethanol, isopropanol or the like.Other suitable solvents may include N,N-dimethylformamide,1-methyl-2-pyrrolidine or the like.

As a further example, a compound of formula (I-E) may be converted to acompound of formula (I-F) using either of two methods.

wherein M³ is B(OH)₂, B(ORa)₂, B(Ra)₂, Sn(Ra)₃, Zn-halide; Zn—Ra orMg-halide, Rg is Ay or Het, and all other variables are as defined inany process described above.

Thus, the present invention provides a process for converting a compoundof formula (I-E) to a compound of formula (I-F) which comprises either:(1) replacing a halogen of the compound of formula (I-E) with an amine;or (2) coupling the compound of formula (I-E) with a metal compound ofthe formula Rg-M³ where M³ is B(OH)₂, B(ORa)₂, B(Ra)₂, Sn(Ra)₃,Zn-halide; Zn-Ra or Mg-halide.

As a further example, a compound of formula (I-G) (i.e., a compound offormula (I) wherein q is 1 or more and at least one R⁵ is O-methyl) maybe converted to a compound of formula (I-H) (i.e., a compound of formula(I) wherein q is 1 or more and at least one R⁵ is OH) using conventionaldemethylation techniques. Additionally, a compound of formula (I-H) mayoptionally be converted to a compound of formula (I-J) (i.e., a compoundof formula (I) wherein q is 1 or more and at least one R⁵ is OR¹⁰). Forexample, the foregoing conversions are represented schematically asfollows:

wherein q′ is 0, 1, 2, 3 or 4; Me is methyl and all other variables aredefined according to any process described above.

The demethylation reaction may be carried out by treating a compound offormula (I-G) in a suitable solvent with a Lewis acid at a temperatureof about −78° C. to room temperature, to produce a compound of formula(I-H). Typically the solvent is an inert solvent such asdichloromethane, chloroform, acetonitrile, toluene or the like. TheLewis acid may be boron tribromide, trimethylsilyl iodide or the like.

Optionally, the compound of formula (I-H) may be further converted to acompound of formula (I-J) by an alkylation reaction. The alkylationreaction may be carried out by treating a compound of formula (I-H) insuitable solvent with an alkyl halide of formula R¹⁰-halo where R¹⁰ isas defined above, to form another compound of formula (I-J). Thereaction is typically carried out in the presence of a base and withoptionally heating to about 50–200° C. The reaction may be carried outin solvents such as N,N-dimethylformamide, dimethylsulfoxide and thelike. Typically the base is potassium carbonate, cesium carbonate,sodium hydride or the like. Additionally, as will be apparent to thoseskilled in the art, the alkylation reaction can be carried out underMitsunobu conditions.

As a further example of methods for converting a compound of formula (I)to another compound of formula (I), a compound of formula (I-K) (i.e., acompound of formula (I) wherein q is 1 or more and at least one R⁵ ishalo) may be converted to a compound of formula (I-L) (i.e., a compoundof formula (I) wherein q is 1 or more and at least one R⁵ is Ay, Het ora nitrogen-linked substituent). for example, the conversion of acompound of formula (I-K) to a compound of formula (I-L) is shownschematically below.

wherein:

-   q′ is 0, 1, 2, 3 or 4;-   R^(5′) is selected from the group consisting of Ay, Het, —NR⁷R⁸,    —NR⁷Ay and —NHHet;-   M⁴ is selected from the group consisting of —B(OH)₂,—B(ORa)₂,    —B(Ra)₂, and —Sn(Ra)₂ wherein Ra is alkyl or cycloalkyl; and-   all other variables are as defined according to any process    described above.

The conversion of a compound of formula (I-K) to a compound of formula(I-L) is carried out by heating a compound of formula (I-K) with acompound of formula H—R^(5′) or coupling the compound of formula (I-K)with a compound of formula R^(5′)-M⁴, where M⁴ is —B(OH)₂,—B(ORa)₂,—B(Ra)₂, —Sn(Ra)₂ wherein Ra is alkyl or cycloalkyl. The reaction may becarried out in an inert solvent, in the presence of a palladium (O)source. The reaction may optionally be heated to about 50–150° C.Preferably the reaction is performed by reacting equimolar amounts of acompound of formula (I-K) with a compound of formula R^(5′)-M⁴. Thereaction may also be performed in the presence of an excess R^(5′)-M⁴.The palladium (O) catalyst is typically present in 1–25 mol % comparedto the compound of formula (I-K). Examples of suitable palladiumcatalysts include but are not limited to,tetrakis(triphenylphosphine)palladium (O),dichlorobis(triphenyl-phosphine)palladium(II), andbis(diphenylphosphinoferrocene)palladium (II) dichloride. Suitablesolvents include but are not limited to, N,N-dimethylformamide, toluene,tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone. When thecompound of formula R^(5′)-M⁴ is a boronic acid or ester or a borinatethe reaction is more conveniently carried out by adding a base in aproportion equivalent to, or greater than, that of the compound offormula R^(5′)-M⁴. Compounds of formula R^(5′)-M⁴ may be obtained fromcommercial sources or prepared either as discreet isolated compounds orgenerated in situ using methods known to one skilled in the art (Suzuki,A. J. Organomet. Chem. 1999, 576, 147; Stille, J. Angew. Chem. Int. Ed.Engl. 1986, 25, 508; Snieckus, V. J. Org. Chem. 1995, 60, 292.)

In yet another example, a compound of formula (I-K) (i.e., a compound offormula (I) wherein q is 1 or more and at least one R⁵ is halo) areconverted to a compound of formula (I-N) (i.e., a compound of formula(I) wherein q is 1 or more and at least one R⁵ is NH₂). Optionally, acompound of formula (I-N) may then be converted to a compound of formula(I-O) (i.e., a compound of formula (I) wherein q is 1 or more and atleast one R⁵ is —NR⁷R⁸ where R⁷ and R⁸ are not both H). For example, theforegoing conversions are represented schematically as follows:

wherein q′ is 0, 1, 2, 3 or 4, and all other variables are definedaccording to any process described above.

The process of converting a compound of formula (I-K) to a compound offormula (I-N) is carried out by reacting a compound of formula (I-K)with an imine in the presence of a palladium (O) source, a base and asuitable ligand, followed by hydrolysis to give a compound of formula(I-N). See J. Wolfe, et al., Tetrahedron Letters 38:6367–6370 (1997).Typically the imine is benzophenoneimine, the palladium (O) source istris(dibenzylideneacetone)dipalladium(O), the base is sodiumtert-butoxide and the ligand isracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Suitable solventsinclude N,N-dimethylformamide and the like.

Reaction of a compound of formula (I-N) with compound of formulaR⁷-halogen in a suitable solvent in the presence of base, optionallywith heating may be used to prepare a compound of formula (I-O).Typically the base is triethylamine or pyridine and the solvent isN,N-dimethylformamide and the like. Other transformations well known tothose skilled in the art for use with anilines may be used to convert acompound of formula (I-N) to a compound of formula (I-O).

Additional compounds of formula (I-O) can be obtained by reductiveamination of a compound of formula (I-N) with ketones or aldehydes. See,K Abdel-Magid, et al., J. Org. Chem. 61:3849–3862 (1996). Typically acompound of formula (I-N) is treated with an aldehyde or a ketone in thepresence of an acid, such as acetic acid, and a reducing agent, such assodium triacetoxyborohydride and the like, in an inert solvent such asdichloroethane and the like.

As previously described, another method for converting a compound offormula (I-K) directly to a compound of formula (I-O) involves heating acompound of formula (I-K) with a amine to thermally displace thehalogen.

In the embodiment where a compound of formula (I),is defined where R¹ isH, the compound of formula (I-P) may be converted to a compound offormula (I-Q). For example, a compound of formula (I-P) may be convertedto a compound of formula (I-Q) by a deprotonation/electrophile quenchprotocol. For example, reaction of a compound of formula (I-P) with abase, such as n-butyllithium, followed by reacting with an electrophilicagent gives a compound of formula (I-Q).

wherein E is selected from halo, alkyl, —C(O)R⁹, —C(O)Ay, —C(O)Het,—CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —S(O)_(n)R⁹ and —R¹⁰cycloalkyl, and allother variables are as defined in connection with any processesdescribed above.

Electrophiles which may be used in this process include, but are notlimited to: halogens (E=iodo, bromo, chloro), alkyl halides (E=methyl,benzyl etc.); aldehydes (E=CH(OH)R¹⁰); dimethylformamide (E=CHO);dialkyl disulfide (E=SMe, SEt, S-isopropyl etc); carbon dioxide(E=CO₂H); dimethylcarbamoyl chloride (E=C(O)NMe₂) and the like.

Typically a compound of formula (I-P) in an inert solvent such astetrahydrofuran at about −78° C. is treated with a nonnucleophilic base.This reaction is subsequently quenched by addition of an electrophile.Suitable nonnucleophilic bases include, but are not limited to,n-butyllithium, lithium diisopropylamide, lithium tetramethylpiperidideand the like.

Further, a compound of formula (I) wherein R¹ is H, may be converted toanother compound of formula (I), by a deprotonation/electrophilequench/nucleophilic displacement protocol. For example, reaction of acompound of formula (I-P) with a base, such as n-butyllithium, followedby quenching with an electrophilic halogenating agent gives a compoundof formula (I-Q where E is halogen) as outlined in the previous scheme.Treatment of a compound of formula (I-Q, where E is halogen) with anucloephile (Z′) in a suitable solvent optionally with heating andoptionally in the presence of a base gives a compound of formula (I-R).

wherein Z¹ is selected from the group consisting of Het, —OR⁷, —OAy,—OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet —S(O)_(n)R⁹ (where n is 0) and cyano andall other variables are as defined according to any process describedabove.

Solvents for use in this reaction include but are not limited totetrahydrofuran, diethylether, and 1-methyl-2-pyrrolidinone. The basemay be sodium hydride, sodium-tert-butoxide, potassium carbonate or thelike.

As another example, one method of converting a compound of formula (I)to another compound of formula (I) comprises a) oxidizing the compoundof formula (I-S), where R¹ is —SR¹⁵ and R¹⁵ is alkyl, cycloalkyl or Ay,to prepare a compound of formula (I-T) and then b) optionally reacting acompound of formula (I-T) with a nucleophile Z¹ selected from the groupconsisting of Het, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet —S(O)_(n)R⁹(where n is 0) and cyano, to prepare a compound of formula (I-U).

wherein Z¹ is selected from the group consisting of Het, —OR⁷, —OAy,—OHet, —NR⁷R⁸ —NR⁷Ay, —NHHet —S(O)_(n)R⁹(where n is 0) and cyano; R¹⁵ isalkyl, cycloalkyl or Ay; and all other variables are as definedaccording to any processes described above.

An analogous method can be used for the conversion of a compound offormula (I) wherein at least one R⁵ is —SR¹⁵ to a compound of formula(I) wherein at least one R⁵ is Z¹.

Based upon this disclosure and the examples contained herein one skilledin the art can readily convert compounds of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof into other compounds of formula (I), or salts,solvates or physiologically functional derivatives thereof.

The present invention also provides radiolabeled compounds of formula(I) and biotinylated compounds of formula (I). Radiolabeled compounds offormula (I) and biotinylated compounds of formula (I) can be preparedusing conventional techniques. For example, radiolabeled compounds offormula (I) can be prepared by reacting the compound of formula (I) withtritium gas in the presence of an appropriate catalyst to produceradiolabeled compounds of formula (I).

In one preferred embodiment, the compounds of formula (I) are tritiated.

The radiolabeled compounds of formula (I) and the biotinylated compoundsof formula (I) are useful in assays for the identification of compoundsfor the treatment or prophylaxis of viral infections such as herpesviral infections. Accordingly, the present invention provides an assaymethod for identifying compounds which have activity for the treatmentor prophylaxis of viral infections such as herpes viral infections,which method comprises the step of specifically binding the radiolabeledcompound of formula (I) or a biotinylated compound of formula (I) to thetarget protein. More specifically, suitable assay methods will includecompetition binding assays. The radiolabeled compounds of formula (I)and biotinylated compounds of formula (I) can be employed in assaysaccording to the methods conventional in the art.

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way. Reagents arecommercially available or are prepared according to procedures in theliterature. Example numbers refer to those compounds listed in thetables above. ¹H and ¹³C NMR spectra were obtained on Varian Unity PlusNMR spectrophotometers at 300 or 400 MHz, and 75 or 100 MHzrespectively. ¹⁹F NMR were recorded at 282 MHz. Mass spectra wereobtained on Micromass Platform, or ZMD mass spectrometers from MicromassLtd. Altrincham, UK, using either Atmospheric Chemical Ionization (APCI)or Electrospray Ionization (ESI). Analytical thin layer chromatographywas used to verify the purity of some intermediates which could not beisolated or which were too unstable for full characterization, and tofollow the progress of reactions. Unless otherwise stated, this was doneusing silica gel (Merck Silica Gel 60 F254). Unless otherwise stated,column chromatography for the purification of some compounds, used MerckSilica gel 60 (230–400 mesh), and the stated solvent system underpressure. All compounds were characterized as their free-base formunless otherwise stated. On occasion the corresponding hydrochloridesalts were formed to generate solids where noted.

Example 1N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine

a) 4-Methyl-2-(methylsulfanyl)pyrimidine.

4-Methylpyrimidine-2-thiol (79.4 g. 488 mmol) was added to 1M aqueoussodium hydroxide (NaOH) (1.02 L, 1.02 mol). To the stirring mixture wasadded iodomethane (76.2 g, 540 mmol) and the reaction-stirred at roomtemperature overnight. The mixture was extracted with dichloromethane(3×300 mL). The organic phase was dried over magnesium sulfate andconcentrated to yield 66.8 g (98%) of4-methyl-2-(methylsulfanyl)pyrimidine. ¹H NMR (CDCl₃): δ 8.39 (d, 1H),6.84 (d, 1H), 2.59 (s, 3H), 2.48 (s, 3H); MS m/z 141 (M+1).

b) 1-(4-Fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone. To a0° C. solution of 4methyl-2-(methylsulfanyl)pyrimidine (66.8 g, 477mmol) and ethyl 4-fluorobenzoate (80.2 g, 477 mmol) in tetrahydrofuran(390 mL) was added a solution of 1M lithium bis(trimethylsilyl)amide(954 mL, 954 mmol) in tetrahydrofuran (THF) dropwise via an additionfunnel. The reaction was stirred for 10 minutes and allowed to warm toroom temperature. The reaction was stirred at room temperature for 1.5hours and then carefully quenched with water. The mixture was extractedwith ethyl acetate (3×300 mL) before the organic phase was dried overmagnesium sulfate, filtered and concentrated. The residue wasrecrystallized from dichloromethane and hexanes to yield 91.4 g (75%) of1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone as amixture of tautomers. Tautomer A: ¹H NMR (CDCl₃): δ 8.50 (d, 1H), 8.12(dd, 2H), 7.18 (m, 2H), 7.02 (d, 1H), 4.39 (s, 2H), 2.56 (s, 3H). MSm/z263 (M+1). Tautomer B: ¹H NMR (CDCl₃): δ 8.35 (d, 1H), 7.87 (dd, 2H),7.16 (m, 3H), 6.68 (d, 1H), 5.96 (s, 1H), 2.65 (s, 3H). MS m/z 263(M+1).

c) 1-(4Fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone oxime.

To a solution of1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone (91.49g,48 mmol) in acetonitrile (1.8 L) was added hydroxylamine hydrochloride(121 g, 91.7 mol) and sodium acetate (139 g, 1.7 mol). The reaction wasstirred for 24 hours before 100 mL of water was added. The reaction wasstirred for 24 hours. The mixture was filtered through a glass frit andthe filtrate partitioned between dichloromethane and water. The layerswere separated and the aqueous phase extracted with dichloromethane(2×500 mL). The organic layers were combined, washed with saturatedaqueous sodium bicarbonate (300 mL), washed with brine (300 mL), driedover magnesium sulfate, filtered and concentrated. The residue wasrecrystalized from dichloromethane and hexanes to yield 66.4 g (69%) of1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone oxime.¹H NMR (CDCl₃): δ 8.75 (m, 1H), 8.42 (d, 1H), 7.75 (dd, 2H), 7.09 (t,2H), 6.98 (d, 1H), 4.29 (s, 2H), 2.54 (s, 3H). MS m/z 278 (M+1).

d) 2-(4-Fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidine.

To a 0° C. solution of1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone oxime(4.0 g, 14 mmol) in ethylene glycol dimethyl ether (40 mL) was addedtrifluoroacetic anhydride (3.0 g, 14 mmol) dropwise. The reaction wasallowed to warm to 20° C., then re-cooled to 0° C. Triethylamine (2.9 g,29 mmol) was added dropwise so that the internal reaction temperaturedid not exceed 10° C. The reaction was allowed to warm to roomtemperature and was stirred for 2 hours. Iron (II) chloride (18 mg, 0.14mmol) was added and the mixture heated to 80° C. for 2 hours. Anadditional portion of iron (II) chloride (18 mg, 0.14 mmol) was addedand the mixture heated at 80° C. for 2 hours. An additional portion ofiron (II) chloride (18 mg, 0.14 mmol) was added and the mixture heatedat 80° C. for 4 hours. The reaction was allowed to cool to roomtemperature and stirred overnight. The mixture was partitioned betweenethyl acetate and water. The aqueous phase was extracted with ethylacetate (2×20 mL) and the organic layers combined. The organic phase waswashed with brine, dried over magnesium sulfate, filtered andconcentrated. The residue was purified by silica chromatography elutingwith 1% acetone in dichloromethane to yield 2.54 g (68%) of2-(4fluorophenyl)-7-(methylsulfanyl)-pyrazolo[1,5-c]pyrimidine. ¹H NMR(CDCl₃): δ 8.04 (dd, 2H),7.80 (d, 1H), 7.20 (m, 3H), 6.79 (s, 1H), 2.76(s, 3H). MS m/z 260 (M+1).

e)1-[2-(4-Fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone.

To a solution of2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidine (150 mg,0.58 mmol) in toluene (10 mL) was added acetic anhydride (0.065 mL, 0.69mmol), followed by boron trifluoride diethyl etherate (0.080 ml, 0.64mmol). An additional 10 mL of toluene was added and the mixture heatedto 90° C. Acetonitrile (10 mL) was added to the reaction and the mixtureheated at 70° C. for additional 16 hours. Additional acetic anhydride(0.11 mL, 1.1 mmol) and boron trifluoride diethyl etherate (0.15 ml, 1.2mmol) were added dropwise to the reaction mixture at 90° C. The reactionwas stirred for 1 hour, cooled to room temperature, stirred for 16hours, and partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. The ethyl acetate layer was washed with brine, driedover magnesium sulfate, filtered, concentrated, and the residue purifiedby silica gel chromatography eluting with 10% ethyl acetate in hexanesto yield 110 mg (63%) of1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone.¹H NMR (CDCl₃): δ 8.13 (d, 1H), 7.98 (d, 1H), 7.65 (dd, 2H), 7.27 (m,2H), 2.77 (s, 3H), 2.23 (s, 3H). MS m/z 302 (M+1).

ee)1-[2-(4fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone.

To a slurry of2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidine (11.8 g,45.5 mmol) in acetic anhydride (250 mL) was added 10 drops of sulfuricacid (H₂SO₄). The mixture was heated at reflux for 2 hours. Additional20 drops of sulfuric acid were added and the reaction heated at refluxfor additional 2 hours. The mixture was allowed to cool and was pouredinto water (300 mL). The mixture was extracted with ethyl acetate (3×200mL). The organic phase was washed with saturated aqueous sodiumbicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated. The residual was co-evaporated with toluene and thendissolved in methylene chloride (CH₂Cl₂). The solution was diluted withhexanes and the resulting precipitate collected by filtration. Thesolids were dissolved in dichloromethane, passed through a silica plugwith 2% acetone in dichloromethane. The wash was concentrated to yield7.5 g of product The filtrate from the initial filtration wasconcentrated and the residue purified by silica chromatography, elutingwith 2% acetone in dichloromethane to yield additional 1.3 g of productThe two portions were combined to yield 8.8 g (64%) of1-[2-(4fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone.

f)1-[7-(Cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone.

To a 0° C. solution of1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone(400 mg, 1.33 mmol) in dichloromethane (10 mL) was added sodiumbicarbonate (110 mg, 1.33 mmol) and 3-chloroperoxybenzoic acid (340 mg,2.00 mmol). The reaction was allowed to warm to room temperature andstirred for 2 hours. The mix was diluted with dichloromethane and theorganic phase was washed with saturated aqueous sodium bicarbonate. Thephases were separated and the organic phase concentrated. The residuewas dissolved in cyclopentylamine (10 mL) and stirred for 2 hours. Thereaction was concentrated and the residue purified by silica gelchromatography eluting with 2% acetone in dichloromethane to give 200 mg(44%) of1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone.¹H NMR (CDCl₃): δ 7.93 (d, 1H), 7.64 (dd, 2H), 7.47 (d, 1H), 7.26 (m,2H), 6.44 (d, 1H), 4.56 (q, 1H), 2.23 (m, 5H), 1.56–1.90 (m, 6H). MS m/z339 (M+1).

g)1-[7-(Cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-one.

To 1-[7-(cyclopentylamino)-2-(4fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone (200 mg, 0.59 mmol) was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (4 mL) and the mixture heated to80° C. for 30 minutes. The reaction was let cool to room temperature andwas partitioned between ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate and the combined organic layers washed withwater and brine. The ethyl acetate solution was dried over magnesiumsulfate, filtered and concentrated. The resulting residue was purifiedby silica chromatography eluting with ethyl acetate to yield 160 mg(69%) of1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-one.¹H NMR (CDCl₃): δ 7.77 (m, 4H), 7.44 (d, 1H), 7.19 (t, 2H), 6.41 (d,1H), 5.09 (d, 1H), 4.57 (m,1H), 3.07 (m, 3H), 2.60 (m, 3H), 2.25 (m,2H), 1.85 (m, 6H). MS m/z 394 (M+1).

h)N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)-pyrazolo[1,5-c]pyrimidin-7-amine.

To a solution of1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-one(160 mg, 0.41 mmol) in N,N-dimethylformamide (10 mL) was addedN-cyclopentylguanidine hydrochloride (130 mg, 0.82 mmol). Freshly groundanhydrous potassium carbonate (56 mg, 0.41 mmol) was added and thereaction heated to 140° C. for 4 hours. Additional freshly groundanhydrous potassium carbonate (120 mg, 0.87 mmol) andN-cyclopentylguanidine hydrochloride (75 mg, 0.46 mmol) were added andthe reaction heated for additional 3 hours. The reaction was allowed tocool and was stirred at room temperature for 16 hours. The mixture wasquenched with water, extracted with ethyl acetate (2×), washed withbrine, concentrated, and the residue purified by silica chromatographyeluting with 5% acetone in dichloromethane to yield 140 mg (75%) ofN-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine.¹H NMR (CDCl₃): δ 8.09 (d, 1H), 7.80 (d, 1H), 7.66 (dd, 2H), 7.54 (d,1H), 7.19 (t, 2H), 6.42 (d, 1H), 6.30 (d, 1H), 5.14 (d, 1H), 4.57 (m,1H), 4.34 (m, 1H), 2.22 (m, 2H), 2.09 (m, 2H), 1.52–1.89 (m, 12H).

Example 2N-Cyclopentyl-3-[2-(cyclopropylamino)pyrimidin-4yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine

The title compound was prepared in a similar manner as described inExample 1 to give a light yellow solid. ¹H NMR (CDCl₃): δ 8.09 (d, 1H),7.77 (d, 1H), 7.68–7.61 (m, 3H), 7.17 (t, 2H), 6.38 (d, 1H), 6.33 (d,1H), 5.43 (broad, 1H), 4.55 (m, 1H), 2.85 (m, 1H), 2.19 (m, 2H),1.83–1.62 (m, 6 H), 0.87 (m, 2 H), 6.63 (m, 2H); ¹⁹F NMR (CDCl₃) δ−112.35; MS m/z 430 (M+1).

Example 34-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine

a) 1-(3-Chlorophenyl)-2-(4pyrimidinyl)ethenol.

To a cold (0° C.) solution of 4-methylpyrimidine (4.56 mL 50.1 mmol) andethyl 3-chlorobenzoate (7.90 mL 50.1 mmol) in tetrahydrofuran (50 mL)was added lithium bis(trimethylsilyl)amide (100 mL, 1.0M intetrahydrofuran, 100 mmol) dropwise over 30 minutes. The resultantmixture was warmed to room temperature and stirred 16 hours. Thereaction mixture was concentrated in vacuo. The resultant oil wasdiluted with methanol. Upon standing, a solid precipitated, which wascollected on a filter to provide1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethenol (11.2 g, 93%) as a yellowsolid. R_(f) 0.31 (3:1 hexanes:ethyl acetate); ¹H NMR (d₆-DMSO) δ 8.37(s, 1H), 7.98 (m, 1H), 7.81–7.76 (m, 2H), 7.38–7.32 (m, 2H), 6.71 (br,1H), 5.65 (s, 1H); MS m/z 233 (M+1).

b) 1-(3-Chlorophenyl)-2-(4-pyrimidinyl)ethanone oxime.

To a suspension of 1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethenol (9.0 g,38.7 mmol) in methanol (100 mL) was added hydroxylamine hydrochloride(11.5 g, 165 mmol) and sodium hydroxide (60 mL, 2.8 M in water, 166mmol). The reaction mixture was refluxed 4 hours. After cooling, theexcess methanol was removed in vacuo. Ice water (˜300 mL) was added tothe resultant mixture and the ice was allowed to melt. The aqueousmixture was extracted with ethyl acetate. The organic layer was washedwith water and brine, then dried over magnesium sulfate. Filtration andconcentration followed by flash chromatography (3:1 to 2:1 hexanes:ethylacetate) provided 1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethanone oxime(6.5 g, 68%) as a white solid. R_(f) 0.14 (3:1 hexanes:ethyl acetate):¹H NMR (CDCl₃) δ 9.50 (br, 1H), 9.18 (s, 1H), 8.61 (d, 1H), 7.78 (s,1H), 7.58 (d, 1H), 7.38–7.25 (m, 3H), 4.38 (s, 2H); MS m/z 248 (M+1).

c) 2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidine.

To a cold (0° C.) solution of1-(3-chlorophenyl)-2-(4-pyrimidinyl)ethanone oxime (5.0 g, 20.2 mmol) inethylene glycol dimethyl ether (50 mL) was added trifluoroaceticanhydride (2.85 ml, 20.2 mmol) dropwise). The reaction mixture waswarmed to room temperature and stirred 10 minutes then recooled to 0° C.A solution of triethylamine (5.63 mL, 40.4 mmol) in ethylene glycoldimethyl ether was added and the resultant solution was stirred at roomtemperature 1.5 hours. Iron (II) chloride (25 mg, 0.20 mmol) was addedand the reaction mixture was refluxed 3 hours. The reaction mixture wascooled to room temperature and the excess ethylene glycol dimethyl etherwas removed in vacuo. The resultant oil was chromatographed (9:1 to 4:1hexanes:ethyl acetate) to provide2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidine (3.2 g, 69%) as a paleyellow solid. R_(f) 0.27 (4:1 hexanes:ethyl acetate); ¹H NMR (CDCl₃) δ9.25 (s, 1H), 8.00 (s, 1H), 7.88–7.81 (m, 2H), 7.46–7.39 (m, 3H), 6.81(s, 1H); MS m/z 230 (M+1).

d) 2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidine-3-carbaldehyde.

To a cold (0° C.) solution of phosphorus oxychloride (1.22 mL, 13.1mmol) in N,N-dimethylformamide (50 mL) was added a solution of2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidine (2.00 g, 8.71 mmol) inN,N-dimethylformamide (25 mL). The reaction mixture was stirred at roomtemperature overnight. To the reaction mixture was added a cold (0° C.)solutions of phosphorus oxychloride (1.22 mL, 13.1 mmol) inN,N-dimethylformamide (50 mL) and the resultant mixture was stirred atroom temperature 4 days. The reaction contents were poured onto ice.After the ice had melted, the precipitated solids were collected on afilter to provide2-(3-chlorophenyl)pyrazolo[1,5c]pyrimidine-3-carbaldehyde (1.5 g, 67%)as a white solid. ¹H NMR (DMSO-d₆) δ 10.11 (s, 1H), 9.86 (s, 1H), 8.37(d, 1H), 8.22 (d, 1H), 7.99 (s, 1H), 7.91 (d, 1H), 7.70–7.59 (m, 2H); MSm/z 258 (M+1).

e) 1-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-ol.

To a solution of2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidine-3-carbaldehyde (1.5 g, 5.82mmol) in tetrahydrofuran (50 mL) was added ethynylmagnesium bromide (17mL, 0.5 M in tetrahydrofuran, 8.73 mmol). The reaction mixture wasstirred 4 hours at room temperature then quenched with water. Themixture was extracted with ethyl acetate. The organic layer was washedwith water and brine, then dried over magnesium sulfate. Filtration andconcentration followed by flash chromatography (2:1 hexanes:ethylacetate) provided1-[2-(3-chlorophenyl)pyrazolo[1.5-c]pyrimidin-3-yl]-2-propyn-1-ol (1.41g, 85%). R_(f) 0.17 (2:1 hexanes:ethyl acetate); ¹H NMR (CDCl₃) δ 9.27(s, 1H), 7.93–7.90 (m, 2H), 7.83 (s, 1H), 7.73 (d, 1H), 7.50–7.41 (m,2H), 5.78 (s, 1H), 2.99 (br, 1H), 2.71 (s, 1H); MS m/z 284 (M+1).

f) 1-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-one.

To a cold (0° C.) solution of1-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-ol (1.41g, 4.97 mmol) in chloroform (600 mL) was added manganese dioxide (30.3g, 0.348 mol). The reaction mixture was stirred at 0° C. for 10 minutesthen filtered through a pad of celite. The filtrate was concentrated invacuo to provide1-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-one (1.40g, 100%) as a white solid. R_(f) 0.37 (2:1 hexanes:ethyl acetate); ¹HNMR (CDCl₃) δ 9.39 (s, 1H), 8.37 (d, 1H), 8.28 (d, 1H), 7.78 (s, 1H),7.62 (d.1H), 7.52–7.40 (m, 2H), 3.17 (s, 1H); MS m/z 282 (M+1).

g) 4-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine.

To a mixture of cyclopentyl guanidine hydrochloride (1.05g, 6.43 mmol)in ethanol (60 mL) was added sodium ethoxide (2.15 mL, 3 M in ethanol,6.43 mmol). The mixture was stirred at room temperature for 30 minutesthen cooled to 0° C. A solution of1-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-one (1.4g, 4.97 mmol) in ethanol (100 mL) was added and the reaction mixture wasstirred at room temperature 16 hours. The reaction mixture was dilutedwith water (200 mL) then concentrated to about two thirds the originalvolume. The precipitated solids were collected on a filter to provide4-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine(1.25 g, 64%) as a white solid. R_(f) 0.19 (4:1 hexanes:ethyl acetate);¹H NMR (CDCl₃) δ9.32 (s,1H), 8.22 (d,1H), 8.13 (d, 1H), 8.01 (d, 1H),7.72 (s,1H), 7.55–7.39 (m, 3H), 6.38 (d,1H), 5.19 (d, 1H), 4.33 (m, 1H),2.08 (m, 2H), 1.80–1.52 (m, 6H); MS m/z 391 (M+1).

Example 44-[2-(3-Chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine

To a cold (−78° C.) solution of4-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentyl-2-pyrimidinamine(267 mg, 0.683 mmol) in tetrahydrofuran (8 mL) was added lithiumdiisopropylamide (12.8 mL, 0.16 M in tetrahydrofuran, 2.05 mmol, madefrom 5 mL n—BuLi (1.6 M in hexanes) and 1.19 mL diisopropylamine in 43.5mL tetrahydrofuran at 0° C.) dropwise. The reaction mixture was stirredat −78° C. for 10 minutes followed by the addition of methyl disulfide(246 μL, 2.73 mmol). The resultant mixture was stirred at −78° C. for 10minutes then quenched with water. Upon warming to room temperature, themixture was extracted with ethyl acetate. The organic layer was washedwith water and brine, then dried over magnesium sulfate. Filtration andconcentration followed by flash chromatography (4:1 to 3:1 hexanes:ethylacetate) provided4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine(171 mg, 57%) as a white solid. R_(f) 0:10 (4:1 hexanes:ethyl acetate);¹H NMR (CDCl₃) δ 8.12 (d, 1H), 7.99–7.91 (m, 2H), 7.73 (s,1H), 7.51 (d,1H), 7.48–7.34 (m, 2H), 6.35 (d,1H), 5.19 (d, 1H), 4.30 (m, 1H), 2.76(s, 3H), 2.05 (m, 2H), 1.82–1.50 (m, 6H); MS m/z 437 (M+1).

Example 52-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-amine

To a cold (0° C.) solution of4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine(40 mg, 0.0915 mmol) in dichloromethane (3 mL) was addedm-chloroperoxybenzoic acid (24 mg, 0.139 mmol). The reaction mixture wasstirred 1.5 hours at 0° C. then diluted with dichloromethane and washedwith saturated aqueous sodium bicarbonate solution. The organic layerwas washed with water and brine, then dried over magnesium sulfate.Filtration and concentration provided a crude oil which was heated incyclopentylamine (2 mL, 20 mmol) at 85° C. in a sealed tube for 16hours. The reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous sodium bicarbonate solution. The organic layerwas washed with brine and dried over magnesium sulfate. Filtration andconcentration followed by flash chromatography (4:1 to 3:1 hexanes:ethylacetate) provided2-(3-chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-amine(28 mg, 65%) as a beige solid. R_(f) 0.27 (3:1 hexanes:ethyl acetate);¹H NMR (CDCl₃) δ 8.09 (d, 1H), 7.78 (d, 1H), 7.71 (s, 1H), 7.51–7.35 (m,4H), 6.41 (d, 1H), 6.30 (d, 1H), 5.15 (d, 1H), 4.53 (m, 1H), 4.29 (m,1H), 2.20 (m, 2H), 2.04 (m, 2H), 1.83–1.50 (m, 12 H); MS m/z 474 (M+1).

Example 64-[2-(3-Chlorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentyl-2-pyrimidinamine

In a similar manner as described in Example 5 from4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine(40 mg, 0.091 mmol),4-[2-(3-chlorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentyl-2-pyrimidinamine(29 mg, 67%) was obtained as a yellow solid. R_(f) 0.18 (2:1hexanes:ethyl acetate); ¹H NMR (CDCl₃) δ 8.10 (d, 1H), 7.78–7.73 (m,2H), 7.68 (t, 1H), 7.52–7.37 (m, 3H), 6.32 (d, 1H), 5.19 (d, 1H), 4.30(m, 1H), 4.04 (m, 4H), 3.93 (m, 4H), 2.05 (m, 2H), 1.79–1.50 (m, 6H); MSm/z 476 (M+1).

Example 72-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described in Example 5 from4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine(40 mg, 0.091 mmol),2-(3-chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)pyrazolo[1,5-c]pyrimidin-7-amine(22 mg, 52%) was obtained as a white solid. R_(f) 0.05 (3:1hexanes:ethyl acetate); ¹H NMR (CDCl₃) δ 8.09 (d, 1H), 7.76–7.69 (m,2H), 7.52–7.36 (m, 4H), 6.74 (t, 1H), 6.32 (d, 1H), 5.13 (d, 1H), 4.29(m,1H), 3.87 (m, 2H), 3.68 (t, 2H), 3.43 (s, 3H), 2.05 (m, 2H),1.79–1.48 (m, 6H); MS m/z 464 (M+1).

Example 82-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-ol

To a cold (0° C.) solution of4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine(90 mg, 0.206 mmol) in dichloromethane (10 mL) was addedm-chloroperoxybenzoic acid (54 mg, 0.313 mmol). The reaction mixture wasstirred 1.5 hours at 0° C. then diluted with dichloromethane and washedwith saturated aqueous sodium bicarbonate. The organic layer was washedwith water and brine, then dried over magnesium sulfate. Filtration andconcentration provided a crude oil. In a separate flask, a solution ofsodium butoxide was prepared by reacting sodium (35 mg, 1.52 mmol) withn-butanol (2 mL). The sodium butoxide solution was added to the crudeoil and the resulting solution was heated in a sealed tube at 120° C.for 16 hours. The reaction mixture was cooled and concentrated in vacuo.The resulting oil was partitioned between water and ethyl acetate. Theorganic layer was washed with water and brine, then dried over magnesiumsulfate. Filtration and concentration provided a crude oil which wasdiluted with ethyl acetate (˜5 mL). Upon standing 7 hours, a solid hadprecipitated, which was collected on a filter to provide2-(3-chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-ol(22 mg, 26%) as a pale yellow solid. ¹H NMR (CDCl₃) δ 8.00 (d, 1H), 7.60(s, 1H), 7.42 (d, 1H), 7.36 (d, 1H), 7.30 (d, 1H), 7.25 (s, 1H), 7.14(d, 1H), 7.02 (d, 1H), 6.24 (d, 1H), 4.19 (m, 1H), 1.99 (m, 2H),1.78–1.42 (m, 6H); MS m/z 407 (M+1).

Example 9N-Cyclopentyl-8-(2-fluoro-4-pyridinyl)-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine

a) Ethyl [(3-phenyl-1H-pyrazol-5-yl)amino]carbothioylcarbamate.

To a cold (0° C.) solution of 3-amino-5-phenylpyrazole (10.0 g, 62.8mmol) in toluene (100 mL) was added ethoxycarbonyl isothiocyanate (8.3mL, 70 mmol) dropwise via a pressure equalizing funnel. Upon completeaddition, the cold bath was removed and the resulting solution wasstirred at room temperature for 15hours, at which time a heavy whiteprecipitate had formed. The precipitate was collected by filtration anddried to give ethyl[(3-phenyl-1H-pyrazol-5-yl)amino]carbothioylcarbamate (11 g, 60%) as awhite solid. ¹H-NMR (DMSO-d₆): δ 13.25 (s, 1H), 12.06 (s, 1H), 11.40 (s,1H), 7.75 (d, 2H), 7.5–7.3 (m, 4H), 4.25 (q, 2H), 1.29 (t, 3H); MS m/z291 (M+1).

b) 7-Phenyl-2-thioxo-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one.

Ethyl [(3-phenyl-1H-pyrazol-5-yl)amino]carbothioylcarbamate (8.4 g, 29mmol) was dissolved in aqueous sodium hydroxide (100 mL, 2N solution)and the resulting solution was stirred at room temperature overnight.This solution was acidified to pH=1 with concentrated sulfuric acid,resulting in heavy precipitation. This precipitate was collected byfiltration and dried to give7-phenyl-2-thioxo-2,3-dihydropyrazolo-[1,5-a][1,3,5]triazin-4(1H)-one(5.7 g, 80%) as a white solid. ¹H-NMR (DMSO-d₆): δ 7.97 (m, 2H), 7.48(m, 3H), 6.41 (s, 1H); MS m/z 245 (M+1).

c) 2-(Methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4(3H)-one.

7-Phenyl-2-thioxo-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H-one (6.4g, 26.2 mmol) was dissolved in absolute ethanol (150 mL). To thissolution was added aqueous sodium hydroxide (2.1 g, 53 mmol in 50 mL ofwater) and finally iodomethane (1.7 mL, 27.3 mmol) was added dropwise.The resulting solution was stirred at room temperature for 3 hours andthen concentrated to a white solid. This solid was suspended in waterand the mixture acidified (to pH=1) with concentrated sulfuric acid. Theresulting precipitate was collected by filtration, washed with water anddried to give2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (5.5g, 81%) as a white solid. ¹H-NMR (DMSO-d₆): δ 7.99 (d, 2H), 7.5 (m, 3H),6.93 (s, 1H), 2.58 (s, 3H); MS m/z 259 (M+1).

d) 4-Chloro-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazine.

2-(Methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4(3H-one (5.4g, 21 mmol) was added to a mixture of phosphorous oxychloride (100 mL)and diethylaniline (2.5 mL). The resulting mixture was-heated at refluxfor 3 hours. The excess phosphorous oxychloride was removed in vacuo andthe dark syrup residue was added slowly to crushed ice with goodstirring. Dichloromethane and water were added and the phases separated.The organic phase was washed with water and brine, dried over magnesiumsulfate, filtered and concentrated to give a crude solid (5 g, 86%). Aportion of this solid was purified by silica gel chromatography (ethylacetate:hexane 1:1) go give a white solid. ¹H-NMR (CDCl₃): δ 8.04 (m,2H), 7.54 (m, 3H), 6.83 (s, 1H), 2.66 (s, 3H); MS m/z 277 (M+1).

e)N-Cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine.

4-Chloro-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazine (2.5g, 9 mmol) was dissolved in cyclopentylamine (30 mL) and the resultingsolution heated to 80° C. for 2 hours. Excess cyclopentylamine wasremoved in vacuo and the residue was dissolved in ethyl acetate. Theorganic phase was washed with water and brine, dried over magnesiumsulfate, filtered and concentrated to give a foam. This foam waspurified by silica gel chromatography (ethyl acetate:hexane 1:1) go give2.3 g (78%) ofN-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4amineas a solid. ¹H-NMR (CDCl₃): δ 7.96 (m, 2H), 7.47 (m, 3H), 6.63 (d, 1H),6.56 (s,1H), 4.54 (m, 1H), 2.61 (s, 3H), 2.2–2.0 (m, 2H), 1.9–1.5 (m,6H); MS m/z 326 (M+1).

f)8—Bromo-N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine.

N-Cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine(0.49 g, 1.5 mmol) was dissolved in dichloromethane. To this solutionwas added N-bromosuccinimide (330 mg, 1.85 mmol) and the resultingsolution was stirred at room temperature for 30 minutes. Additionaldichloromethane was added and the reaction mixture was extracted with 1Naqueous sodium hydroxide and with water. The organic phase was dried(magnesium sulfate), filtered and concentrated to give a solid. Thissolid was purified by silica gel chromatography (ethyl acetate:hexane1:2) to give 0.5 g (82%) of8-bromo-N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amineas a solid. ¹H-NMR (CDCl₃): δ 8.05 (m,2H), 7.55 (m,3H), 6.52 (d, 1H),4.60 (m,1H), 2.66 (s, 3H), 2.3–2.1 (m, 2H), 2.0–1.6 (m, 6H); MS m/z 405(M+1).

g)N-Cyclopentyl-8-(2-fluoro-4-pyridinyl)-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine.

8—Bromo-N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine(0.20 g, 0.50 mmol) was dissolved in N,N-dimthylformamide. To thissolution was added dichlorobis(triphenylphosphine)palladium (II] (70 mg,0.2 equiv), anhydrous sodium carbonate (105 mg, 2 equiv),2-fluoro-4-pyridinylboronic acid (91 mg, 1.3 equiv) and a few drops ofwater. The reaction mixture was heated at 100° C. for 12 hours, at whichtime no starting material remained in the reaction mixture. Ethylacetate and water were added to the reaction mixture. The phases wereseparated and the organic phase was washed with water, dried overmagnesium sulfate, filtered and concentrated. Purification by silica gelchromatography (ethyl acetate:hexane 1:1) gave 70 mg (33%) ofN-cyclopentyl-8-(2-fluoro-4pyridinyl)-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amineas a white foam. ¹H-NMR (CDCl₃): δ 8.10 (d, 1H), 7.60 (m, 2H), 7.52 (m,3H), 7.37 (m, 1H), 7.29 (s, 1H), 6.55 (d, 1H), 4.63 (m, 1H), 2.66 (s,3H), 2.3–2.1 (m, 2H), 2.0–1.6 (m, 6H);F-NMR (CDCl₃): δ −69.01; MS m/z421 (M+1).

Example 10N²,N⁴-Dicyclopentyl-8-[2-(cyclopentylamino)-4-pyridinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

N-Cyclopentyl-8-(2-fluoro-4-pyridiny)-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4amine 60 mg, 0.14 mmol) was dissolved in cyclopentylamine and heatedat 160° C. in a glass pressure vessel for 24 hours. The resultingsolution was concentrated in vacuo to give a residue that was purifiedby silica gel chromatography (ethyl acetate:hexane 1:1 to ethyl acetate)to yield 25 mg (34%) ofN²,N⁴-dicyclopentyl-8-[2-(cyclopentylamino)-4-pyridinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamineas a foam. ¹H-NMR (CDCl₃): δ 7.94 (d, 1H), 7.60 (m, 2H), 7.45 (m, 3H),6.81 (d, 1H), 6.36 (m, 1H), 5.13 (d, 1H), 4.60 (m, 1H), 4.44 (m, 2H),3.74 (m, 1H), 2.1–1.4 (m, 24H); MS m/z 523 (M+1).

Example 11N-Cyclopentyl-8-[2-(cyclopentylamino)-4-pyrimidinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine

a) N-Cyclopentyl-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine.

N-Cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine(300 mg, 0.92 mmol, from Example 9) was dissolved in absolute ethanol(30 mL). To this mixture was added Raney nickel (approximately 2–3 g)and the reaction was heated at reflux for 6 hours. The Raney nickel wasremoved by filtering the reaction mixture through a Celite pad, and theCelite was washed with ethanol (150 mL). The combined organic phase wasconcentrated to dryness. The resulting residue was purified by silicagel chromatography (ethyl acetate:hexane 1:1) to give 200 mg (78%) ofN-cyclopentyl-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine as a yellowfoam. ¹H-NMR (CDCl₃): δ 8.24 (s, 1H), 7.98 (m, 2H), 7.51 (m, 3H), 6.75(s, 1H), 6.67 (d, 1H), 4.60 (m, 1H), 2.3–2.1 (m, 2H), 2.0–1.6 (m, 6H);MS m/z 280 (M+1).

b) N—Cyclopentyl-8-iodo-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4amine.

N-Cyclopentyl-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4amine (0.25 g, 0.90mmol) was dissolved in dichlorornethane. To this solution was addedN-iodosuccinimide (300 mg, 1.33 mmol) and the resulting solution wasstirred at room temperature for 30 minutes. Additional dichloromethanewas added and the reaction mixture was extracted with 1N aqueous sodiumhydroxide and with water. The organic phase was dried (magnesiumsulfate), filtered and concentrated to give a solid. This solid waspurified by silica gel chromatography (ethyl acetate:hexane 1:1) to give310 mg (85%) ofN-cyclopentyl-8-iodo-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine as ayellow solid. ¹H-NMR (CDCl₃): δ 8.35 (s, 1H), 7.98 (m, 2H), 7.55 (m,3H), 6.64 (d, 1H), 4.60 (m, 1H), 2.3–2.1 (m, 2H), 2.0–1.6 (m, 6H); MSm/z 406 (M+1).

c)N-Cyclopentyl-8-[2-(cyclopentylamino)-4-pyrimidinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine.

N-Cyclopentyl-8-iodo-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine (80mg, 0.20 mmol) was dissolved in anhydrous toluene (5 mL). To thissolution was added 2-(methylsulfanyl)-4-(tributylstannyl)pyrimidine (100mg, 0.24 mmol,) and dichlorobis(triphenylphosphine)palladium (II] (14mg, 0.1 equiv) and the resulting mixture heated at 100° C. for 24 hours.Ethyl acetate and water were added to the reaction mixture. The phaseswere separated and the organic phase washed with water, dried overmagnesium sulfate, filtered and concentrated. Purification by silica gelchromatography (ethyl acetate:hexane 1:1) gave an inseparable mixture ofthe desiredN-cyclopentyl-8-[2-(methylsulfanyl)-4-pyrimidinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-aminecontaminated withN-cyclopentyl-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine. Thismixture was dissolved in dichloromethane (15 mL) and3-chloroperoxybenzoic acid (113 mg, 57–86%) was added. The resultingreaction mixture was stirred at room temperature for 1 hour.Dichloromethane and saturated aqueous potassium carbonate were added andthe phases separated. The organic phase was washed with additionalsaturated aqueous potassium carbonate, water, dried over magnesiumsulfate, filtered and concentrated to give a foam. This foam wasdissolved in cyclopentylamine and the solution was heated at 60° C. for3 hours. The mixture was concentrated in vacuo and the residue purifiedby silica gel chromatography (ethyl acetate:hexane 1:1) to give 20 mg(23% for 3 steps) ofN-cyclopentyl-8-[2-(cyclopentylamino)-4-pyrimidinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amineas a white foam. ¹H-NMR (CDCl₃): δ 8.39 (s, 1H), 8.28 (d, 1H), 7.67 (m,2H), 7.46 (3H), 6.71 (d, 1H), 5.01 (d, 1H), 4.64 (m, 1H), 3.80 (m, 1H),1.2–2.3 (m, 16H); MS m/z 441 (M+1).

Example 123-[2-(Butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described in Example 1 above,3-[2-(butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine(80 mg, 72%) was prepared from1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-oneand N-butylguanidine. ¹H NMR (CDCl₃): δ 8.04 (d, 1H), 7.74 (d, 1H), 7.60(dd, 2H), 7.48 (d, 1H), 7.13 (t, 2H), 6.36 (d, 1H), 6.25 (d, 1H), 5.05(t, 1H), 4.51 (m, 1H), 3.42 (qt, 2H), 2.16 (m, 2H), 1.78 (m, 2H),1.56–1.70 (m, 6H), 1.43 (m, 2H), 0.95 (t, 3H). MS m/z 446 (M+1).

Example 133-(2-Anilinopyrimidin-4-yl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo-[1,5-c]pyrimidin-7-amine

In a similar manner as described above,3-(2-anilinopyrimidin-4-yl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine(70 mg, 60%) was prepared from1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-oneand N-cyclopentylguanidine. ¹H NMR (CDCl₃): δ 8.19 (d, 1H), 7.72 (d,1H), 7.62 (dd, 2H), 7.57 (dd, 2H), 7.44 (d, 1H), 7.30 (t, 2H), 7.15 (t,2H), 7.08 (s, 1H), 7.03 (t, 1H), 6.47 (d, 1H), 6.38 (d, 1H), 4.52 (m,1H), 2.12–2.24 (m, 2H), 1.79 (m, 2H), 1.60–1.72 (m, 4H). MS m/z466(M+1).

Example 143-[2-(1,3-Benzothiazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described above,3-[2-(1,3-benzothiazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine(38 mg, 29%) was prepared from1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-oneand N-(1,3-benzothiazol-2-yl)guanidine. ¹H NMR (CDCl3): δ 10.58 (bs,1H), 8.49 (d, 1H), 7.90 (d, 1H), 7.75 (d, 1H), 7.73 (d, 1H), 7.64 (dd,2H), 7.47 (d, 1H), 7.40 (t, 1H), 7.23 (t, 1H), 7.15 (t, 2H), 6.69 (d,1H), 6.41 (d, 1H), 4.54 (m, 1H), 2.14–2.24 (m, 2H), 1.58–1.85 (m, 6H).MS m/z 523 (M+1).

Example 15N-Cyclopentyl-2-(4-fluorophenyl)-3-{2-[(4-methyl-1,3-thiazol-2-yl)amino]pyrimidin-4-yl}pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described above,N-cyclopentyl-2-(4-fluorophenyl)-3-{2-[(4-methyl-1,3-thiazol-2-yl)amino]pyrimidin-4-yl}pyrazolo[1,5-c]pyrimidin-7-amine(65 mg, 53%) was prepared from1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-oneand N-(4-methyl-1,3-thiazol-2-yl)guanidine. ¹H NMR (CDCl3): δ 9.16 (s,1H), 8.33 (d, 1H), 7.76 (d, 1H), 7.61 (dd, 2H), 7.45 (d, 1H), 7.14 (t,2H), 6.58 (d, 1H), 6.40 (s, 1H), 6.39 (d, 1H), 4.53 (m, 1H), 2.35, (s,3H), 2.13–2.24 (m, 2H), 1.60–1.84 (m, 6H). MS m/z 487 (M+1).

Example 163-[2-(1H-Benzimidazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described above,3-[2-(1H-benzimidazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine(18 mg, 14%) was prepared from1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-oneand N-(1H-benzimidazol-2-yl)guanidine. ¹H NMR (CDCl₃): δ 8.40 (m, 1H),7.80 (d, 1H), 7.66 (m, 3H), 7.37 (m, 1H), 7.17 (m, 7H), 6.71 (m, 1H),6.44 (m, 1H), 4.56 (m, 1H), 2.18 (m, 2H), 1.62–1.87 (m, 6H). MS m/z 506(M+1).

Example 17N-Cyclopentyl-3-{2-[(4-fluorobenzyl)amino]pyrimidin-4-yl}-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described above,N-cyclopentyl-3-{2-[(4-fluorobenzyl)amino]pyrimidin-4-yl}-2-(4fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine(21 mg, 17%) was prepared from1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-oneand N-(4-fluorobenzyl)guanidine trifluoroacetate. ¹H NMR (CDCl₃): δ 8.07(d, 1H), 1.64 (d, 1H), 7.59 (dd, 2H), 7.33 (dd, 2H), 7.21 (bs, 1H), 7.13(t, 2H), 7.02 (t, 2H), 6.34 (d, 1H), 6.31 (d, 1H), 5.42 (t, 1H), 4.62(d, 2H), 4.49 (m, 1H), 2.11–2.20 (m, 2H) 1.74–1.83 (m, 2H), 1.59–1.72(m, 4H). MS m/z 498 (M+1).

Example 18N-Cyclopentyl-2-(4-fluorophenyl)-3-{2-[(2-phenylethyl)amino]pyrimidin-4yl}pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described above,N-cyclopentyl-2-(4-fluorophenyl)-3-{2-[(2-phenylethyl)amino]pyrimidin-4-yl}pyrazolo[1,5-c]pyrimidin-7-amine (9 mg, 7%) was prepared from1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-oneand N-(2-phenylethyl)guanidine sulfate. ¹H NMR (CDCl₃): δ 8.05 (d, 1H),7.73 (d, 1H), 7.61 (dd, 2H), 7.48 (d, 1H), 7.31 (m, 2H), 7.23 (m, 3H),7.13 (t, 2H), 6.37 (d, 1H), 6.28 (d, 1H). 5.14 (t, 1H), 4.51 (m, 1H),3.71 (q, 2H), 2.94 (t, 2H), 2.16 (m, 2H), 1.75–1.85 (m, 2H), 1.62–1.73(m, 4H). MS m/z494 (M+1).

Example 193-[2-(tert-Butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine

a) Methyl N-(tert-butyl)imidothiocarbamate hydroiodide

To a solution of t-butylthiourea (1.35 g, 10.2 mmol) in methanol (150mL) was added iodomethane (2.13 g, 15.0 mmol). The solution was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure to yield the title compound (2.8 g, >99%) as ayellow solid. ¹H NMR (CDCl₃): δ 9.07 (s, 1H), 8.6 (bs, 2H), 2.63 (s,3H), 1.40 (s, 9H). MS m/z 147 (M+1).

b) N-(tert-Butyl)guanidine hydroiodide

N-(tert-Butyl)imidothiocarbamate hydroiodide (2.8 g, 10 mmol) wasdissolved in a 2M NH3 solution in methanol (100 mL). The reactionmixture was heated to reflux for 3 hours and then removed from heat tostir at room temperature for 48 hours. The reaction mixture wasconcentrated under reduced pressure to leave the title compound (2.4g, >99%) as a solid.

c)3-[2-(tert-Butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described above,3-[2-(tert-butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine(29 mg, 26%) was prepared from1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-oneand N-(tert-butyl)guanidine hydroiodide. ¹H NMR (CDCl₃): δ 58.10 (d,1H), 7.78 (d, 1H), 7.64 (dd, 2H), 7.45 (d, 1H), 7.17 (t, 2H), 6.42 (d,1H), 6.31 (d, 1H), 5.16 (s, 1H), 4.56 (m, 1H), 2.22 (m, 2H), 1.63–1.90(m, 15H). MS m/z 446 (M+1).

Example 20N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine

a)1-[2-(4Fluorophenyl)-7-methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone

To a slurry of2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidine (1.5 g,5.9 mmol) in acetic anhydride (10 mL) was added 4 drops of sulfuricacid. The reaction mixture was heated to 80° C. for 2 hours, to 110° C.for 2 hours, and to reflux for 2 hours. The solution was allowed to coolto room temperature and stirred for 4 days. The mixture was poured intowater (350 mL) and extracted with ethyl acetate (2×75 mL). The organicphase was washed with brine and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 2:98acetone:dichloromethane to yield1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone(1.24 g, 70%). ¹H NMR (DMSO): δ 8.12 (d, 1H), 7.98 (d, 1H), 7.65 (dd,2H), 7.24 (m, 2H), 2.77 (s, 3H), 2.23 (s, 3H). MS m/z302 (M+1).

b)(2E)-3-(Dimethylamino)-1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo-[1,5-c]pyrimidin-3-yl]prop-2-en-1-one

To1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone(1.24 g, 4.12 mmol) was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine(15 mL) and the mixture heated to 120° C. for 1 hour. The reaction wasallowed to cool to room temperature and stirred for 16 hours. Themixture was diluted with hexanes. The precipitate was collected byfiltration and air dried to yield(2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]prop-2-en-1-one(880 mg, 60%). ¹H NMR (DMSO): δ 8.03 (d, 1H), 7.72–7.82 (m, 3H), 7.57(d, 1H), 7.37 (t, 2H), 5.08 (d, 1H), 3.04 (bs, 3H), 2.71 (s, 3H), 2.52(bs, 3H). MS m/z 357 (M+1).

c)N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine

To a solution of(2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]prop-2-en-1-one(660 mg, 1.85 mmol) and N-cyclopentylguanidine hydrochloride (600 mg,3.71 mmol) in N,N-dimethylformamide (10 mL) was added potassiumcarbonate (760 mg, 5.55 mmol). The reaction mixture was heated to 100°C. for 1 hour and then to 115° C. for 4 hours. The reaction was allowedto cool to room temperature and diluted with water. The mixture wasextracted with ethyl acetate, washed with brine, dried over magnesiumsulfate, filtered and concentrated. The residue was purified usingsilica gel chromatography eluting with 50% acetone in dichloromethane toyieldN-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine(210 mg, 32%). ¹H NMR (CDCl₃): δ 8.05(d,1H), 7.94 (m, 2H), 7.64 (dd,2H), 7.13 (t, 2H), 6.29 (d, 1H), 5.21 (bs, 1H), 4.31 (m, 1H), 2.72 (s,3H), 2.06 (m, 2H), 1.49–1.82 (m, 6H). MS m/z 421 (M+1).

Example 21N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described aboveN-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-amine(610 mg, 66%) was prepared as a brown solid. ¹H NMR (CDCl₃) δ 8.02 (d,1H), 7.73 (d, 1H), 7.57–7.52 (m, 3H), 6.98 (d, 2H), 6.40 (d, 1H), 6.30(d, 1H), 5.12 (d, 1H), 4.51 (m, 1H), 4.32 (m, 1H), 3.87 (s, 3H),2.18–2.03 (m, 4H), 1.81–1.49 (m, 12H); MS m/z 470 (M+1).

Example 224-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-c]pyrimidin-2-yl}phenol

In a similar manner as described above4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-c]pyrimidin-2-yl}phenol (535 mg, 90%) was prepared as a yellow solid. ¹H NMR (DMSO) δ9.82 (s, 1H), 8.02 (d, 1H), 7.84–7.77 (m, 2H), 7.40 (d, 2H), 6.88 (d,2H), 6.27 (m, 1H), 4.51–4.44 (m, 1H), 1.99–1.93 (m, 3H), 1.73–1.55 (m,11H), 1.27–1.24 (m, 3H), 0.88–0.83 (m, 2H); MS m/z 456 (M+1).

Example 23N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described aboveN-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-c]pyrimidin-7-amine(170 mg, 76%) was prepared as a brown solid. ¹H NMR (CDCl₃) δ 8.02 (d,1H), 7.73 (d, 1H), 7.55–7.52 (m, 3H), 6.99–6.96 (m, 2H), 6.39 (d, 1H),6.30 (d, 1H), 5.05 (d, 1H), 4.54–4.49 (m, 1H), 4.35–4.30 (m, 1H), 3.86(d, 2H), 2.18–2.05 (m, 3H), 1.80–1.60 (m, 7H), 1.56–1.51 (m, 7H),0.68–0.65 (m. 2H), 0.39–0.37 (m, 2H); MS m/z 510 (M+1).

Example 243-[2-(Cyclopentylamino)pyrimidin-4-yl]-N-cyclopropyl-2-(4-methoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described above3-[2-(cyclopentylamino)pyrimidin-4-yl]-N-cyclopropyl-2-(4methoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-amine(150 mg, 56%) was prepared as a white solid. ¹H NMR (CDCl₃) δ 8.03 (d,1H), 7.813 (d, 1H), 7.60 (m, 1H), 7.55–7.52 (m, 2H), 6.99–6.96 (m, 2H),6.63 (m,1H), 6.30 (d, 1H), 5.09 (m, 1H), 4.33 (m, 1H), 3.87 (s, 3H),2.99 (m, 1H), 2.09–2.04 (m, 3H), 1.77–1.65 (m, 5H), 0.97–0.92 (m, 2H),0.78–0.74 (m, 2H); MS m/Z 442 (M+1).

Example 252-(4-Butoxyphenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described above2-(4-butoxyphenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-c]pyrimidin-7-amine was prepared as a whitesolid. ¹H NMR (CDCl₃) δ 8.02 (d, 1H), 7.73 (d, 1H), 7.55–7.52 (m, 3H),6.97 (m, 2H), 6.40 (d, 1H), 6.31 (d, 1H), 5.09 (d, 1H), 4.51 (m, 1H),4.32 (m, 1H), 4.02 (t, 2H), 2.19–2.04 (m, 5H), 1.85–1.48 (m, 15H), 0.99(m, 3H); MS m/z 512 (M+1).

Example 26N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described aboveN-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-aminewas prepared as a tan solid. ¹H NMR (CDCl₃), δ 8.02 (d, 1H), 7.73 (d,1H), 7.55–7.52 (m, 3H), 6.97 (m, 2H), 6.39 (d, 1H), 6.31 (d, 1H), 5.07(d, 1H), 4.51 (m, 1H), 4.33 (m, 1H), 3.77 (d, 2H), 2.19–2.04 (m, 5H),1.79–1.49 (m, 12H), 1.05(d, 6H); MS m/z 512 (M+1).

Example 27N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-[4-(2-methoxyethoxy)phenyl]pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described aboveN-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-[4-(2-methoxyethoxy)phenyl]pyrazolo[1,5-c]pyrimidin-7-aminewas prepared as a yellow solid. ¹H NMR (CDCl₃) δ 8.02 (d, 1H), 7.73 (d,1H), 7.55–7.52 (m, 3H), 7.00 (m, 2H), 6.39 (d, 1H), 6.27 (d, 1H), 5.10(d, 1H), 4.51 (m, 1H), 4.33 (m, 1H), 4.18 (m, 2H), 3.78 (m, 2H), 3.47(s, 3H), 2.18–2.03 (m, 4H), 1.78–1.49 (m, 12H); MS m/z 514 (M+1).

Example 28N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-propoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-amine

In a similar manner as described aboveN-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4yl]-2-(4-propoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-aminewas prepared as a yellow solid. ¹H NMR (CDCl₃) δ 8.02 (d, 1H), 7.73 (d,1H), 7.55–7.52 (m, 3H), 6.97 (m, 2H), 6.40 (d, 1H), 6.31 (d, 1H), 5.10(d, 1H), 4.5 (m, 1H), 4.33 (m, 1H), 3.98 (t, 2H), 2.19–2.05 (m, 1H),1.87–1.5 (m, 14H), 1.06 (t, 3H); MS m/z 498 (M+1).

Example 29N-(tert-Butyl)-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine

To a solution ofN-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine(40 mg, 0.095 mmol) in dichloromethane (2 mL) was added3-chloroperoxybenzoic acid (12 mg, 0.14 mmol) and the reaction mixturestirred at room temperature for 1 hour. t-Butylamine (3 mL) was addedand heated to reflux for 3 hours. The reaction was allowed to cool anddiluted with water. The mixture was extracted with ethyl acetate and theorganic phase washed with brine before being concentrated under vacuum.The residue was purified by silica gel chromatography eluting with SO/5acetone in dichloromethane to yield a 1:1 mixture of starting materialand product. The residue was dissolved in dichloromethane (2 mL) and3-chloroperoxybenzoic acid (18 mg, 0.21 mmol) was added. The mixture wasstirred for 2 hours and then t-butylamine (3 mL) was added. The reactionmixture was stirred for 3 hours, diluted with water, extracted withethyl acetate, washed with brine, concentrated, and the residue purifiedby silica gel chromatography eluting with 5% acetone in dichloromethaneto yieldN-(tert-butyl)-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine(6 mg, 14%), ¹H NMR (CDCl₃): δ 8.02 (d, 1H), 7.72 (d, 1H), 7.60 (dd,2H), 7.47 (d, 1H), 7.13 (t, 2H), 6.42 (s, 1H), 6.25 (d, 1H), 5.14 (bs,1H), 4.28 (m, 1H), 2.04 (m, 2H), 1.45–1.78 (m, 15H). MS m/z 446 (M+1).

Example 30N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-pyrrolidin-1-ylpyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine

To a solution ofN-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine(24 mg, 0.057 mmol) in dichloromethane (3 mL) was added3-chloroperoxybenzoic acid (15mg, 0.086 mmol) and the reaction mixturestirred for 1 hour. Pyrrolidine (3 mL) was added and the reactionmixture stirred for 2 hours before being diluted with dichloromethane.The organic phase was washed with saturated sodium bicarbonate, washedwith brine, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 5% acetone indichloromethane to yieldN-cyclopentyl-4-[2-(4-fluorophenyl)-7-pyrrolidin-1-ylpyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine(15 mg, 59%). ¹H NMR (CDCl₃): δ 8.05 (d, 1H), 7.65 (d, 1H), 7.60 (dd,2H), 7.43 (d,1H), 7.10 (t, 2H), 6.27 (d, 1H), 5.05 (d, 1H), 4.29 (m,1H), 4.09 (t, 4H), 1.99 (m, 6H), 1.45–1.78 (m, 6H). MS m/z 444 (M+1).

Example 31N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-piperidin-1-ylpyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine

In a similar manner as described above,N-cyclopentyl-4-[2-(4-fluorophenyl)-7-piperidin-1-ylpyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine(25 mg, 45%) was prepared fromN-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amineand piperidine. ¹H NMR (CDCl₃): δ 8.06 (d, 1H), 7.73 (d, 1H), 7.63 (m,3H), 7.11 (t, 2H), 6.29 (d,1H), 5.08 (m,1H) 4.29 (m,1H),3.91 (m, 4H),2.05 (m, 2H), 1.68–1.80 (m, 9H), 1.63 (m, 1H), 1.51 (m,2H). MS m/z 458(M+1).

Example 32 Biological Activity

In the following example, “MEM” means Minimal Essential Media; “FBS”means Fetal Bovine Serum; “NP40” and “Igepal” are detergents; “MOI”means Multiplicity of Infection; “NaOH” means sodium hydroxide; “MgCl₂”means magnesium chloride; “dATP” means deoxyadenosine 5′ triphosphate;“dUTP” means deoxyuridine 5′ triphosphate; “dCTP” means dexoxycytidine5′ triphosphate; “dGTP” means deoxyguanosine 5′ triphosphate; “GuSCN”means Guanidinium thiocyanate; “EDTA” means ethylenediamine tetraaceticacid; “T” means Tris-EDTA; “SCC” means sodium chloride/sodium citrate;“APE” means a solution of ammonia acetate, ammonia phosphate, EDTA;“PBS” means phosphate buffered saline; and “HRP” means horseradishperoxidase.

a) Tissue Culture and HSV infection.

Vero 76 cells were maintained in MEM with Earle's salts, L-glutamine, 8%FBS (Hyclone, A-1111-L) and 100 units/mL Penicillin-100 μg/mLStreptomycin. For assay conditions, FBS was reduced to 2%. Cells areseeded into 96-well tissue culture plates at a density of 5×10⁴cells/well after being incubated for 45 min at 37° C. in the presence ofHSV-1 or HSV-2 (MOI=0.001). Test compounds are added to the wells andthe plates are incubated at 37° C. for 40–48 hours. Cell lysates areprepared as follows: media was removed and replaced with 150 μL/well 0.2N NaOH with 1% Igepal CA 630 or NP-40. Plates were incubated up to 14days at room temperature in a humidified chamber to prevent evaporation.

(b) Preparation of detection DNA.

For the detection probe, a gel-purified, digoxigenin-labeled, 710-bp PCRfragment of the HSV UL-15 sequence was utilized. PCR conditions included0.5 μM primers, 180 μM dTTP, 20 μM dUTP-digoxigenin (Boehringer Mannheim1558706), 200 μM each of dATP, dCTP, and dGTP, 1×PCR Buffer II (PerkinElmer), 2.5 mM, MgCl₂, 0.025 units/μL of AmpliTaq Gold polyerase (PerkinElmer), and 5 ng a gel-purified HSV DNA per 100 μL Extension conditionswere 10 min at 95° C., followed by 30 cycles of 95° C. for 1 min, 55° C.for 30 sec, and 72° C. for 2 min. The amplification was completed with a10-min incubation at 72° C. Primers were selected to amplify a 728 bpprobe spanning a section of the HSV1 UL15 open reading frame(nucleotides 249–977). Single-stranded transcripts were purified withPromega M13 Wizard kits. The final product was mixed 1:1 with a mixtureof 6 M GuSCN, 100 mM EDTA and 200 μg/mL herring sperm DNA and stored at4° C.

(c) Preparation of capture plates.

The capture DNA plasmid (HSV UL13 region in pUC) was linearized bycutting with Xba I, denatured for 15 min at 95° C. and dilutedimmediately into Reacti-Bind DNA Coating Solution (Pierce, 17250,diluted 1:1 with TE buffer, pH 8) at 1 ng/μL 75 μl/well were added toCorning (#3922 or 9690) white 96-well plates and incubated at roomtemperature for at least 4 hrs before washing twice with 300 μL/well0.2×SSC/0.05% Tween-20 (SSC/T buffer). The plates were then incubatedovernight at room temperature with 150 μL/well 0.2 N NaOH, 1% IGEPAL and10 μg/mL herring sperm DNA.

(d) Hybridization.

Twenty-seven (27) μL of cell lysate was combined with 45 μL ofhydridization solution (final concentration: 3M GuSCN, 50 mM EDTA, 100μg/ml salmon sperm DNA, 5× Denhardt's solution, 0.25× APE, and 5 ng ofthe digoxigenin-labeled detection probe). APE is 1.5 M NH₄-acetate, 0.15M NH₄H₂phosphate, and 5 mM EDTA adjusted to pH 6.0. Mineral oil (50 μL)was added to prevent evaporation. The hybridization plates wereincubated at 95° C. for 10 minutes to denature the DNA, then incubatedat 42° C. overnight. The wells were washed 6× with 300 μL/well SSC/Tbuffer then incubated with 75 μL/well anti-digoxigenin-HRP-conjugatedantibody (Boehringer Mannheim 1207733, 1:5000 in TE) for 30 min at roomtemperature. The wells were washed 6× with 300 μL/well with PBS/0.05%Tween-20 before 75 μL/well SuperSignal LBA substrate (Pierce) was added.The plates were incubated at room temperature for 30 minutes andchemiluminescence was measured in a Wallac Vietor reader.

e) Results.

The following results were obtained for HSV-1.

Example No. IC₅₀ (μM) 1 0.72 2 5.5 3 3.9 4 11.3 5 0.46 6 0.20 7 0.30 82.5 9 7.1 10 0.12 11 6.4 12 1 13 1.5 14 >40 15 >40 16 >40 17 2 18 3.5 193 20 >40 21 0.4 22 4 23 0.5 24 1 25 0.6 26 0.5 27 1 28 0.5 29 7 30 2 311

The results demonstrate that the compounds of the present invention areuseful for the treatment and prophylaxis of herpes viral infections.

1. A compound of formula (I):

wherein: R¹ is selected from the group consisting of H, halo, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay,—C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸,—C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹,—S(O)_(n)Ay, —S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl,—R¹⁰Ay, —R¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹, —R¹⁰C(O)R⁹,—R¹⁰C(O)Ay, —R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹, —R¹⁰OC(O)Ay,—R¹⁰OC(O)Het, —R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰SO₂NHCOR⁹, —R¹⁰OS(O)_(n)R⁹, cyano, nitro and azido; each R⁷ and R⁸are the same or different and are independently selected from the groupconsisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, —C(O)R⁹,—CO₂R⁹, —C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂R¹⁰, —SO₂NR⁹R¹¹,—R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰NHCOR⁹, —R¹⁰NHC(NH)NR⁹R¹¹,—R¹⁰C(NH)NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R¹⁰ and—R¹⁰SO₂NHCOR⁹; each R⁹ and R¹¹ are the same or different and areindependently selected from the group consisting of H, alkyl,cycloalkyl, —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰), where w is 1–10, and—R¹⁰NR¹⁰R¹⁰; each R¹⁰ is the same or different and is independentlyselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl, and alkynyl; n is 0, 1 or 2; Ay is aryl; Het is a 5- or6-membered heterocyclic or heteroaryl group; Y¹ is CH; p is 0, 1 or 2when Y¹ is CH, each R⁶ is the same or different and is independentlyselected from the group consisting of H, halo, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷,—OAy, —OHet, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het,—R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰NHSO₂R⁹, —R¹⁰C(O)R⁹, —R¹⁰C(O)Ay,—R¹⁰C(O)Het, —R¹⁰CO₂R⁹, —R¹⁰OC(O)R⁹, —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het,—R¹⁰C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰C(NH)NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹,—R¹⁰OS(O)_(n)R⁹, cyano, nitro and azido; Y is N or CH; R² is selectedfrom the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NHHet,—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ and R⁴ are thesame or different and are each independently selected from the groupconsisting of H, halo, alkyl, alkenyl, cycloalkyl, Ay, Het, —C(O)R⁷,C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy, —NR⁷R⁸, —NR⁷Ay, —NHHet, —SO₂NHR⁹,—R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; Ring A isselected from the group consisting of aryl, 5–10 membered heterocyclicgroup and a 5–10 membered heteroaryl group; q is 0, 1, 2, 3, 4 or 5; andeach R⁵ is the same or different and is independently selected from thegroup consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, Ay, Het, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸,—C(O)NR⁷Ay, —C(S)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —OR⁷, —OAy, —OHet,—NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—R¹⁰cycloalkyl, —R¹⁰Het, —R¹⁰C(O)R⁹, —R¹⁰CO₂R⁹, —R¹⁰C(O)NR⁹R¹¹,—R¹⁰C(O)NR⁷Ay, —R¹⁰C(O)NHR¹⁰Het, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹,—R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰SO₂R⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂NHCOR⁹,cyano, nitro and azido; or a pharmaceutically acceptable salt, thereof.2. The compound according to claim 1 wherein R¹ is selected from thegroup consisting of halo, alkyl, cycloalkyl, Ay, Het, —OR⁷, —OAy,—NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —R¹⁰cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸and —R¹⁰NR⁷Ay.
 3. The compound according to claim 1 wherein R¹ isselected from the group consisting of alkyl, Het, —OR⁷, —NR⁷R⁸, —NR⁷Ayand —S(O)_(n)R⁹.
 4. The compound according to claim 1 wherein p is 0or
 1. 5. The compound according to claim 1 wherein each R⁶ is the sameor different and is independently selected from the group consisting ofhalo, alkyl, Ay, Het, —C(O)Het, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —OR⁷,—OAy, —NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het,—R¹⁰OR⁹ and cyano.
 6. The compound according to claim 1 wherein each R⁶is the same or different and is independently selected from the groupconsisting of halo, alkyl, Het, —NR⁷R⁸, —NHHet and —S(O)_(n)R⁹.
 7. Thecompound according to claim 1 wherein Y is CH.
 8. The compound accordingto claim 1 wherein Y is N.
 9. The compound according to claim 1 whereinR² is selected from the group consisting of Ay, Het, —OR⁷, —OAy, —OHet,—NR⁷R⁸, —NR⁷Ay, —NHHet, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and—R¹⁰NR⁷Ay.
 10. The compound according to claim 1 wherein R² is selectedfrom the group consisting of —NR⁷R⁸, —NR⁷Ay and —NHHet.
 11. The compoundaccording to claim 1 wherein R³ and R⁴ are the same or different and areeach independently selected from the group consisting of H, halo, alkyl,Ay, —CO₂R⁷, —OR⁷, —NR⁷R⁸, —R¹⁰NR⁷ and —R¹⁰NR⁷R⁸.
 12. The compoundaccording to claim 1 wherein R³ and R⁴ are both H.
 13. The compoundaccording to claim 1 wherein Ring A is selected from the groupconsisting of aryl, a 5–6 membered heterocyclic or heteroaryl group anda 9-membered heterocyclic or heteroaryl group.
 14. The compoundaccording to claim 1 wherein Ring A is selected from the groupconsisting of phenyl, naphthyl, furan, pyridine, pyrimidine, thiazol,pyrazine, pyrrole, imidazole, oxazole, benzimidazole, quinoline,isoquinoline and quinoxoline.
 15. The compound according to claim 1wherein Ring A is selected from the group consisting of phenyl, furan,pyridine and pyrimidine.
 16. The compound according to claim 1 whereinRing A is phenyl.
 17. The compound according to claim 1 wherein q is 0,1 or
 2. 18. The compound according to claim 1 wherein each R⁵ is thesame or different and is independently selected from the groupconsisting of halo, alkyl, alkenyl, Ay, Het, —CO₂R⁹, —C(O)NR⁷R⁸,—C(O)NR⁷Ay, —OR⁷, —OAy, —NR⁷R⁸, —NR⁷Ay, —S(O)₂NR⁷R⁸, cyano, nitro andazido.
 19. The compound according to claim 1 wherein each R⁵ is the sameor different and is independently selected from the group consisting ofhalo, alkyl, —OR⁷, —NR⁷R⁸ and cyano.
 20. A compound selected from thegroup consisting of:N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;N-Cyclopentyl-3-[2-(cyclopropylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;4-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine;4-[2-(3-Chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine;2-(3-Chlorophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-amine;4-[2-(3-Chlorophenyl)-7-(4-morpholinyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentyl-2-pyrimidinamine;2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)pyrazolo[1,5-c]pyrimidin-7-amine;2-(3-Chlorophenyl)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-c]pyrimidin-7-ol;3-[2-(Butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;3-(2-Anilinopyrimidin-4-yl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;3-[2-(1,3-Benzothiazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;N-Cyclopentyl-2-(4-fluorophenyl)-3-{2-[(4-methyl-1,3-thiazol-2-yl)amino]pyrimidin-4-yl}pyrazolo[1,5-c]pyrimidin-7-amine;3-[2-(1H-Benzimidazol-2-ylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;N-Cyclopentyl-3-{2-[(4-fluorobenzyl)amino]pyrimidin-4-yl}-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;N-Cyclopentyl-2-(4-fluorophenyl)-3-{2-[(2-phenylethyl)amino]pyrimidin-4-yl}pyrazolo[1,5-c]pyrimidin-7-amine;3-[2-(tert-Butylamino)pyrimidin-4-yl]-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine;N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-amine;4-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-c]pyrimidin-2-yl}phenol;3-[2-(Cyclopentylamino)pyrimidin-4-yl]-N-cyclopropyl-2-(4-methoxyphenyl)pyrazolo-[1,5-c]pyrimidin-7-amine;2-(4-Butoxyphenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]pyrazolo[1,5-c]pyrimidin-7-amine;N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-isobutoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-amine;N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-[4-(2-methoxyethoxy)phenyl]pyrazolo[1,5-c]pyrimidin-7-amine;N-Cyclopentyl-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-propoxyphenyl)pyrazolo[1,5-c]pyrimidin-7-amine;N-(tert-Butyl)-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine;N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-pyrrolidin-1-ylpyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine;andN-Cyclopentyl-4-[2-(4-fluorophenyl)-7-piperidin-1-ylpyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine,or a pharmaceutically acceptable salt, thereof.
 21. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically acceptable carrier.
 22. The pharmaceutical compositionaccording to claim 21 further comprising an antiviral agent selectedfrom the group consisting of aciclovir and valaciclovir.
 23. A methodfor the treatment of a herpes viral infection selected from herpessimplex virus 1 and herpes simplex virus 2, in an animal, said methodcomprising administering to the animal a therapeutically effectiveamount of a compound according to claim
 1. 24. A method for thetreatment of a condition or disease associated with a herpes viralinfection selected from herpes simplex virus 1 and herpes simplex virus2, in an animal, comprising administering to the animal atherapeutically effective amount of the compound of formula (I)according to claim
 1. 25. A process for preparing a compound accordingto claim 1 wherein Y¹ is CH; Y is N; R² is selected from the groupconsisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, Ay, Het, —OR⁷,—OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NH Het —S(O)_(n)R⁹, —S(O)_(n)Ay, R¹⁰NR⁷R⁸and —R¹⁰NR⁷Ay; and R³ and R⁴ are H, said process comprising reacting acompound of formula (XX):

with a compound of formula (XXI):


26. A process for preparing a compound according to claim 1 wherein Y isN; R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NHHet—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; R³ is selected fromthe group consisting of H, alkyl, alkenyl, cycloalkyl, Ay, Het, —C(O)R⁷,C(O)Ay, —CO₂R⁷, —CO₂Ay, —OR⁷, —OAy, —NR⁷R⁸ (where R⁷ and R⁸ are not H),—NR⁷Ay (where R⁷ is H), —SO₂NHR⁹, —R¹⁰OR⁷, —R¹⁰cycloalkyl, —R¹⁰OAy,—R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay; and R⁴ is H said process comprising reacting acompound of formula (XXV):

with a compound of formula (XXI):


27. A process for preparing a compound according to claim 1 wherein Y isN and R² is selected from the group consisting of alkyl, cycloalkyl,alkenyl, cycloalkenyl, Ay, Het, —OR⁷, —OAy, —OHet —NR⁷R⁸, —NR⁷Ay, —NHHet—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸ and —R¹⁰NR⁷Ay, said processcomprising the steps of: a) reacting a compound of formula (XXVIII):

with a compound of formula (XXI):

to prepare an intermediate compound; and b) oxidizing the intermediatecompound.
 28. A process for preparing a compound according to claim 1comprising reacting a compound of formula (XXX):

wherein X¹ is chloro, bromo or iodo; with a compound of formula (X):

wherein M¹ is —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, orMg-halide where Ra is alkyl or cycloalkyl and halide is halo.